What are the Patterns Between Depression, Smoking, Unhealthy Alcohol Use, and Other Substance Use Among Individuals Receiving Medical Care? A Longitudinal Study of 5479 Participants.
To evaluate and characterize the structure of temporal patterns of depression, smoking, unhealthy alcohol use, and other substance use among individuals receiving medical care, and to inform discussion about whether integrated screening and treatment strategies for these conditions are warranted. Using the Veterans Aging Cohort Study (VACS) we measured depression, smoking, unhealthy alcohol use and other substance use (stimulants, marijuana, heroin, opioids) and evaluated which conditions tended to co-occur within individuals, and how this co-occurrence was temporally structured (i.e. concurrently, sequentially, or discordantly). Current depression was associated with current use of every substance examined with the exception of unhealthy alcohol use. Current unhealthy alcohol use and marijuana use were also consistently associated. Current status was strongly predicted by prior status (p < 0.0001; OR = 2.99-22.34) however, there were few other sequential relationships. Associations in the HIV infected and uninfected subgroups were largely the same with the following exceptions. Smoking preceded unhealthy alcohol use and current smoking was associated with current depression in the HIV infected subgroup only (p < 0.001; OR = 1.33-1.41 and p < 0.001; OR = 1.25-1.43). Opioid use and current unhealthy alcohol use were negatively associated only in the HIV negative subgroup (p = 0.01; OR = 0.75). Patterns of depression, smoking, unhealthy alcohol use, and other substance use were temporally concordant, particularly with regard to depression and substance use. These patterns may inform future development of more integrated screening and treatment strategies.


Potential of Ambient Sensor Systems for Early Detection of Health Problems in Older Adults.
Background: Home monitoring sensor systems are increasingly used to monitor seniors in their apartments for detection of emergency situations. The aim of this study was to deliver a proof-of-concept for the use of multimodal sensor systems with pervasive computing technology for the detection of clinically relevant health problems over longer time periods. Methods: Data were collected with a longitudinal home monitoring study in Switzerland (StrongAge Cohort Study) in a cohort of 24 old and oldest-old, community-dwelling adults over a period of 1 to 2 years. Physical activity in the apartment, toilet visits, refrigerator use, and entrance door openings were quantified using a commercially available passive infrared motion sensing system (Domosafety S.A., Switzerland). Heart rate, respiration rate, and sleep quality were recorded with the commercially available EMFIT QS bed sensor device (Emfit Ltd., Finland). Vital signs and contextual data were collected using a wearable sensor on the upper arm (Everion, Biovotion, Switzerland). Sensor data were correlated with health-related data collected from the weekly visits of the seniors by health professionals, including information about physical, psychological, cognitive, and behavior status, health problems, diseases, medication, and medical diagnoses. Results: Twenty of the 24 recruited participants (age 88.9 ± 7.5 years, 79% females) completed the study; two participants had to stop their study participation because of severe health deterioration, whereas two participants died during the course of the study. A history of chronic disease was present in 12/24 seniors, including heart failure, heart rhythm disturbances, pulmonary embolism, severe insulin-dependent diabetes, and Parkinson's disease. In total, 242,232 person-hours were recorded. During the monitoring period, 963 health status records were reported and repeated clinical assessments of aging-relevant indicators and outcomes were performed. Several episodes of health deterioration, including heart failure worsening and heart rhythm disturbances, could be captured by sensor signals from different sources. Conclusions: Our results indicate that monitoring of seniors with a multimodal sensor and pervasive computing system over longer time periods is feasible and well-accepted, with a great potential for detection of health deterioration. Further studies are necessary to evaluate the full range of the clinical potential of these findings.


Benchmarking Cellulose Nanocrystals: From the Laboratory to Industrial Production.
The renewability, biocompatibility, and mechanical properties of cellulose nanocrystals (CNCs) have made them an attractive material for numerous composite, biomedical, and rheological applications. However, for CNCs to shift from a laboratory curiosity to commercial applications, researchers must transition from CNCs extracted on the bench scale to material produced on an industrial scale. There are a number of companies currently producing kilogram to ton per day quantities of sulfuric acid-hydrolyzed CNCs as well as other nanocelluloses, as described herein. With the recent intensification of industrially produced CNCs and the variety of cellulose sources, hydrolysis methods, and purification procedures, the characterization of these materials becomes critical. This has further been justified by the past two decades of research that demonstrate that the CNC stability and behavior are highly dependent on the surface chemistry, surface charge density, and particle size. This work outlines key test methods that should be employed to characterize these properties to ensure a "known" starting material and consistent performance. Of the sulfuric acid-extracted CNCs examined, industrially produced material compared well with laboratory-made CNCs, exhibiting similar charge density, colloidal and thermal stability, crystallinity, morphology, and self-assembly behavior. In addition, it was observed that further purification of CNCs using Soxhlet extraction in ethanol had minimal impact on the nanoparticle properties and is unlikely to be necessary for many applications. Overall, the current standing of industrially produced CNCs is positive, suggesting that the evolution to commercial-scale applications will not be hindered by CNC production.


Tenofovir nephrotoxicity: 2011 update.
Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study.


A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss.
Primary microcephaly is a genetically heterogeneous condition characterized by reduced head circumference (-3 SDS or more) and mild-to-moderate learning disability. Here, we describe clinical and molecular investigations of a microcephalic child with sensorineural hearing loss. Although consanguinity was unreported initially, detection of 13.7 Mb of copy neutral loss of heterozygosity (cnLOH) on chromosome 9 implicated the CDK5RAP2 gene. Targeted sequencing identified a homozygous E234X mutation, only the third mutation to be described in CDK5RAP2, the first in an individual of non-Pakistani descent. Sensorineural hearing loss is not generally considered to be consistent with autosomal recessive microcephaly and therefore it seems likely that the deafness in this individual is caused by the co-occurrence of a further gene mutation, independent of CDK5RAP2. Nevertheless, further detailed clinical descriptions of rare CDK5RAP2 patients, including hearing assessments will be needed to resolve fully the phenotypic range associated with mutations in this gene. This study also highlights the utility of SNP-array testing to guide disease gene identification where an autosomal recessive condition is plausible.


Multibuilding Block Janus Synthesized by Seed-Mediated Self-Assembly for Enhanced Photothermal Effects and Colored Brownian Motion in an Optical Trap.
The asymmetrical features and unique properties of multibuilding block Janus nanostructures (JNSs) provide superior functions for biomedical applications. However, their production process is very challenging. This problem has hampered the progress of JNS research and the exploration of their applications. In this study, an asymmetrical multibuilding block gold/iron oxide JNS has been generated to enhance photothermal effects and display colored Brownian motion in an optical trap. JNS is formed by seed-mediated self-assembly of nanoparticle-loaded thermocleavable micelles, where the hydrophobic backbones of the polymer are disrupted at high temperatures, resulting in secondary self-assembly and structural rearrangement. The JNS significantly enhances photothermal effects compared to their homogeneous counterpart after near-infrared (NIR) light irradiation. The asymmetrical distribution of gold and iron oxide within JNS also generates uneven thermophoretic force to display active colored Brownian rotational motion in a single-beam gradient optical trap. These properties indicate that the asymmetrical JNS could be employed as a strong photothermal therapy mediator and a fuel-free nanoscale Janus motor under NIR light.


Magnesium and hypertension.
Essential hypertension (EHT) is one of the most common risk factors for cerebrovascular and cardiovascular disease (CVD), which in turn are among the most common causes of death and disability in developed countries. Drug treatment of EHT has proven effective in lessening the risk of CVD, but has attendant risk of side effects, some of which are of risk to the CV system. Thus, increasing attention is being paid to non-drug treatment of EHT, which includes changing the daily intake of such electrolytes as sodium (Na), potassium (K), calcium (Ca), and magnesium (Mg). Decreasing Na intake to control blood pressure (BP) is well established. On the basis of epidemiologic and experimental studies, increasing K and/or Mg intakes, and increasing of decreasing Ca intakes, have each been proposed to have beneficial effects of BP. Presented here is a review of the background data supporting the rationale for adding Mg to the anti-hypertensive regimen. There is evidence that Mg can exert a favorable effect in EHT, particularly when used in combination with K during diuretic therapy.


Percutaneous Coronary Intervention in the Elderly: Are Drug-coated Balloons the Future?
Balloon angioplasty revolutionised percutaneous treatment for coronary artery disease four decades ago, but vessel-threatening dissections, elastic recoil and restenosis were major drawbacks to an otherwise successful long-lasting intervention. Subsequent advances with bare metal stents and then drug eluting stents followed, aiming to mitigate the risks of acute vessel closure and restenosis. However, stent implantation often necessitates dual antiplatelet therapy for a prolonged period of time, which in itself can lead to adverse outcomes, especially in the frail elderly population at higher risk of bleeding. More recently, bioabsorbable stents have been implemented in clinical practice enabling earlier intimal coverage of the stent and apposition. However, another addition to the armamentarium of percutaneous coronary intervention is the use of drug-coated balloons without the need for deploying any coronary stents or scaffolds. Drugcoated balloons are semi-compliant balloons coated with an antiproliferative agent that is rapidly released on contact with the vessel intima exerting an anti-restenotic effect. The absence of a metallic scaffold means that the need for antiplatelet therapy can potentially be negated in the longer term if required. In this article, we will review the history of percutaneous coronary intervention and the available evidence for the appropriate use of drug-coated balloons especially in the elderly population. We will conclude this review by demonstrating the potential use of drug-coated balloon rather percutaneous stenting through case examples.


Characterising the complexity of medication safety using a human factors approach: an observational study in two intensive care units.
To examine medication safety in two intensive care units (ICU), and to assess the complexity of medication errors and adverse drug events (ADE) in ICUs across the stages of the medication-management process. Four trained nurse data collectors gathered data on medication errors and ADEs between October 2006 and March 2007. Patient care documents (eg, medication order sheets, notes) and incident reports were used to identify medication errors and ADEs in a 24-bed adult medical/surgical ICU and an 18-bed cardiac ICU in a tertiary care, community teaching hospital. In this cross-sectional study, a total of 630 consecutive ICU patient admissions were assessed to produce data on the number, rates and types of potential and preventable ADEs across stages of the medication-management process. An average of 2.9 preventable or potential ADEs occurred in each admission, that is, 0.4 events per patient-day. Preventable or potential ADEs occurred in 2.6% of the medication orders. The rate of potential ADEs per 1000 patient-days was 276, whereas the rate of preventable ADEs per 1000 patient-days was 9.2. Most medication errors occur at the ordering (32%) and administration stages (39%). In 16-24% of potential and preventable ADEs, clusters of errors occurred either as a sequence of errors (eg, delay in medication dispensing leading to delay in medication administration) or grouped errors (eg, route and frequency errors in the order for a medication). Many of the sequences led to administration errors that were caused by errors earlier in the medication-management process. Understanding the complexity of the vulnerabilities of the medication-management process is important to devise solutions to improve patient safety. Electronic health record technology with computerised physician order entry may be one step necessary to improve medication safety in ICUs. Solutions that target multiple stages of the medication-management process are necessary to address sequential errors.


Cellular Interrogation: Exploiting Cell-to-Cell Variability to Discriminate Regulatory Mechanisms in Oscillatory Signalling.
The molecular complexity within a cell may be seen as an evolutionary response to the external complexity of the cell's environment. This suggests that the external environment may be harnessed to interrogate the cell's internal molecular architecture. Cells, however, are not only nonlinear and non-stationary, but also exhibit heterogeneous responses within a clonal, isogenic population. In effect, each cell undertakes its own experiment. Here, we develop a method of cellular interrogation using programmable microfluidic devices which exploits the additional information present in cell-to-cell variation, without requiring model parameters to be fitted to data. We focussed on Ca2+ signalling in response to hormone stimulation, which exhibits oscillatory spiking in many cell types and chose eight models of Ca2+ signalling networks which exhibit similar behaviour in simulation. We developed a nonlinear frequency analysis for non-stationary responses, which could classify models into groups under parameter variation, but found that this question alone was unable to distinguish critical feedback loops. We further developed a nonlinear amplitude analysis and found that the combination of both questions ruled out six of the models as inconsistent with the experimentally-observed dynamics and heterogeneity. The two models that survived the double interrogation were mathematically different but schematically identical and yielded the same unexpected predictions that we confirmed experimentally. Further analysis showed that subtle mathematical details can markedly influence non-stationary responses under parameter variation, emphasising the difficulty of finding a "correct" model. By developing questions for the pathway being studied, and designing more versatile microfluidics, cellular interrogation holds promise as a systematic strategy that can complement direct intervention by genetics or pharmacology.


Frequency of the erythrogenic toxin B and C genes (speB and speC) among clinical isolates of group A streptococci.
DNA probes corresponding to the internal region of the erythrogenic toxin B and C genes, speB and speC, were used in hybridization studies with clinical isolates of Streptococcus pyogenes to determine the frequency of occurrence of these genes in a large population of group A streptococci. More than 500 strains from different geographical locations throughout the world were used in this study. The results from colony-lift hybridization experiments indicated that the frequency of occurrence of each toxin gene among all of these strains was 100% for speB and 50% for speC. Division of these strains into subgroups of general group A strains and strains associated with scarlet fever or rheumatic fever resulted in a frequency of occurrence of speC of about 50% for all subgroups. The speC gene was found to be more frequently associated with serotype M2, M4, and M6 strains and less frequently associated with serotype M1, M3, and M49 strains. The results from a similar study with the speA gene have been previously reported (C.-E. Yu and J.J. Ferretti, Infect. Immun. 57:3715-3719, 1989).


A wireless body area network of intelligent motion sensors for computer assisted physical rehabilitation.
BACKGROUND: Recent technological advances in integrated circuits, wireless communications, and physiological sensing allow miniature, lightweight, ultra-low power, intelligent monitoring devices. A number of these devices can be integrated into a Wireless Body Area Network (WBAN), a new enabling technology for health monitoring. METHODS: Using off-the-shelf wireless sensors we designed a prototype WBAN which features a standard ZigBee compliant radio and a common set of physiological, kinetic, and environmental sensors. RESULTS: We introduce a multi-tier telemedicine system and describe how we optimized our prototype WBAN implementation for computer-assisted physical rehabilitation applications and ambulatory monitoring. The system performs real-time analysis of sensors' data, provides guidance and feedback to the user, and can generate warnings based on the user's state, level of activity, and environmental conditions. In addition, all recorded information can be transferred to medical servers via the Internet and seamlessly integrated into the user's electronic medical record and research databases. CONCLUSION: WBANs promise inexpensive, unobtrusive, and unsupervised ambulatory monitoring during normal daily activities for prolonged periods of time. To make this technology ubiquitous and affordable, a number of challenging issues should be resolved, such as system design, configuration and customization, seamless integration, standardization, further utilization of common off-the-shelf components, security and privacy, and social issues.


Mouse models for inherited endocrine and metabolic disorders.
In vivo models represent important resources for investigating the physiological mechanisms underlying endocrine and metabolic disorders, and for pre-clinical translational studies that may include the assessments of new treatments. In the study of endocrine diseases, which affect multiple organs, in vivo models provide specific advantages over in vitro models, which are limited to investigation of isolated systems. In recent years, the mouse has become the popular choice for developing such in vivo mammalian models, as it has a genome that shares ∼85% identity to that of man, and has many physiological systems that are similar to those in man. Moreover, methods have been developed to alter the expression of genes in the mouse, thereby generating models for human diseases, which may be due to loss- or gain-of-function mutations. The methods used to generate mutations in the mouse genome include: chemical mutagenesis; conventional, conditional and inducible knockout models; knockin models and transgenic models, and these strategies are often complementary. This review describes some of the different strategies that are utilised for generating mouse models. In addition, some mouse models that have been successfully generated by these methods for some human hereditary endocrine and metabolic disorders are reviewed. In particular, the mouse models generated for parathyroid disorders, which include: the multiple endocrine neoplasias; hyperparathyroidism-jaw tumour syndrome; disorders of the calcium-sensing receptor and forms of inherited hypoparathyroidism are discussed. The advances that have been made in our understanding of the mechanisms of these human diseases by investigations of these mouse models are described.


MMP-2-responsive fluorescent nanoprobes for enhanced selectivity of tumor cell uptake and imaging.
It is difficult to develop highly selective substrate-based fluorescent nanoprobes for specific matrix metalloproteinases (MMPs) due to overlapping substrate specificities among the family of MMP enzymes. To resolve this issue, we have developed novel fluorescent nanoprobes that are highly selective for soluble MMP-2. Herein, MMP-2-responsive nanoprobes were prepared by immobilizing fluorescent fusion proteins on nickel ferrite nanoparticles via the His-tag nickel chelation mechanism. The fusion protein consisted of a fluorescent mCherry protein with a cell penetrating peptide (CPP) moiety. An MMP-2 cleavage site was also introduced within the fusion protein, which was directly linked to the nickel ferrite nanoparticles. The selectivity of nanoprobes was modulated by hiding the cleavage site of MMP-2 substrates deeply inside the system, which could result in strong steric hindrance between the nanoprobes and MMPs, especially for membrane-tethered MMPs such as MMP-14. A cell-based assay demonstrated that the nanoprobes could only be activated by tumor cells secreting soluble MMP-2, but not membrane-tethered MMP-14. To further evaluate the contribution of the steric hindrance effect on the nanoprobes, a truncated recombinant MMP-14 was employed to confer their cleavage activity as compared to native membrane-tethered MMP-14. Furthermore, a designed probe with a diminished steric hindrance effect was proved to be activated by membrane-tethered type MMP-14. The results indicated that the design of fluorescent nanoprobes employing the steric hindrance effect can greatly enhance the selectivity of MMP-responsive nanoprobes realizing the specific detection of soluble MMP-2 in a tumor microenvironment. We believe that highly selective MMP-2-responsive fluorescent nanoprobes have broad impacts on biomedical applications including molecular imaging and labeling for tumor detection.


Identification of Trypanosoma cruzi trans-sialidase family members as targets of protective CD8+ TC1 responses.
CD8+ T lymphocytes play a critical role in immunity to Trypanosoma cruzi. However, the target molecules of this T cell subset have not been elucidated. In this work, we report the identification of an H-2Kb-restricted CTL epitope within two trypomastigote surface Ags encoded by members of the T. cruzi sialidase/trans-sialidase gene superfamily. Octapeptide VDYNFTIV sensitized target cells for lysis by CD8+ CTL generated from spleens of T. cruzi-infected mice. Peptide-specific CD8+ T cell lines were cytotoxic, secreted IFN-gamma and TNF-alpha, but low to undetectable levels of IL-4 and IL-5, and were able, upon adoptive transfer, to confer a high degree of protection against challenge infection. Finally, the protective determinant appears to be conserved among parasites from diverse geographic locations. This constitutes the first identified class I MHC-restricted epitope in T. cruzi and provides the basis for the search of additional targets to be considered in the development of vaccines against Chagas' disease.


Delivering trials in the NHS: more than worth it.
Randomised trials are the best method to determine the efficacy and safety of health technologies. A recent report by Lord O'Shaughnessy highlighted many of the current challenges to delivering trials in the UK and proposed potential solutions. Among these, making trials the business of all NHS institutions and a valued part of all doctors' work, while leveraging the potential of the data that the NHS collects routinely, offers an opportunity to improve NHS efficiency, doctors' job satisfaction and population health simultaneously.


Effect of CFIm25 knockout on RNA polymerase II transcription.
Transcription of eukaryotic protein-coding genes by RNA polymerase II (pol II) is a highly regulated process. Most human genes have multiple poly(A) sites, which define different possible mRNA ends, suggesting the existence of mechanisms that regulate which poly(A) site is used. Poly(A) site selection may be mediated by cleavage factor I (CFIm), which is part of the cleavage and polyadenylation (CPA) complex. CFIm comprises CFIm25, CFIm59 and CFim68 subunits. It has been documented that the CPA complex also regulates pol II transcription at the start of genes. We therefore investigated whether CFIm, in addition to its role in poly(A) site selection, is involved in the regulation of pol II transcription. We provide genome-wide data of the effect of reducing by 90% expression of the CFIm25 constituent of CFIm, which is involved in pre-mRNA cleavage and polyadenylation, on pol II transcription in human cells. We performed pol II ChIP-seq in the presence or absence of CFIm25 and with or without an inhibitor of the cyclin-dependent kinase (CDK)9, which regulates the entry of pol II into productive elongation.


Primary hypothalamic lymphoma with panhypopituitarism presenting as stiff-man syndrome.
We report an unusual case of primary hypothalamic lymphoma with hypopituitarism presenting as Stiff-man syndrome (SMS). A 64-year-old man was hospitalized due to a 3-week history of general weakness, anorexia, vomiting, weight loss, and muscle pain and spasms precipitated by motion and tactile stimuli resulting in muscle stiffness and difficulty in mobility. Physical examination revealed normal sensorimotor function and reflexes, except for bitemporal visual field defect. Routine laboratory and gastrointestinal examinations provided no remarkable clues. Endocrine assessment revealed low levels of morning cortisol, thyroxine, and anterior pituitary hormones but an increase in prolactin level. The patient's muscle pain and stiffness improved dramatically within 2 days after hydrocortisone therapy and thyroxine replacement. Magnetic resonance imaging (MRI) of the brain confirmed an 18-mm enhancing hypothalamic tumor with optic chiasm involvement, which proved to be a B-cell lymphoma. The results of the extensive studies for systemic lymphoma were negative, suggesting a primary hypothalamic lymphoma. The tumor regressed completely and was invisible on MRI scan after adjuvant radiotherapy. The patient's condition was satisfactory and there was no recurrence of SMS during the 2-year follow-up period. This case demonstrated that primary hypothalamic lymphoma complicated with adrenal insufficiency may manifest as SMS. Early diagnosis and prompt intervention can lead to a favorable outcome and reduce morbidity.


Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab.
ATTRACTION-2 demonstrated that nivolumab improved overall survival (OS) vs placebo in patients with advanced gastric cancer treated with ≥ 2 chemotherapy regimens. However, its long-term efficacy and outcome of treatment beyond progression (TBP) with nivolumab have not been clarified. The 3-year follow-up data were collected. A subset analysis was performed to explore the efficacy of TBP by assessing postprogression survival (PPS) after the first event of disease progression. Overall, 493 patients were randomized (2:1) to receive nivolumab (n = 330) or placebo (n = 163). With a median follow-up of 38.5 (range 36.1-47.5) months, OS of the nivolumab group was significantly longer compared to the placebo group (median 5.3 vs 4.1 months; 3-year survival rate, 5.6% vs 1.9%; hazard ratio [HR], 0.62 [95% confidence interval (CI) 0.50-0.75], P < 0.0001). The median OS of responders (n = 32) who achieved complete response or partial response was 26.7 months and the 3-year survival rate was 35.5% in the nivolumab group. Overall, 109 patients in the nivolumab group and 37 patients in the placebo group received TBP. PPS tended to be longer in the nivolumab group vs placebo group (median 5.8 vs 4.5 months; HR [95% CI], 0.69 [0.47-1.01], P = 0.057). In contrast, PPS was similar between both treatment groups in non-TBP patients (median 2.3 vs 2.2 months; HR 0.90, P = 0.42). Long-term efficacy of nivolumab was confirmed at the 3-year follow-up, and a survival benefit of TBP with nivolumab was suggested. Biomarkers for selecting patients suitable for TBP with nivolumab should be identified in the future.


Management of hypertension in high school students by using new salt titrator tape.
In a blood pressure screening program involving 6589 high school students, 180 male (4.7%) and 17 female (0.6%) students were identified as borderline hypertensive. The 174 hypertensive male adolescents studied further showed pathophysiological features such as a significantly higher frequency of obesity, higher 24-hour urinary sodium excretion, higher hematocrit value, higher sodium and lower potassium concentration in red blood cells, and higher ouabain-sensitive sodium efflux compared with the control group (231 male students; p less than 0.05). When used alone, the ordinary 10-week period of counseling about a low salt diet failed to significantly reduce the blood pressure of hypertensive students. However, when education and counseling efforts were combined with self-monitoring of salt (chloride) excretion in overnight urine samples using a new salt titrator tape developed in our laboratory, 24-hour urinary sodium excretion, weight, and blood pressure decreased significantly over 10 weeks (mean reduction: 52 mEq/day for 24-hour urinary sodium excretion, 1.7 kg for weight, 12/7 mm Hg for blood pressure). These results indicate that blood pressure of borderline hypertensive adolescents could be effectively reduced with this nonpharmacological method of dietary education. Such systematic management might be of importance for the prevention of essential hypertension.


The effect of anthropogenic arsenic contamination on the earthworm microbiome.
Earthworms are globally distributed and perform essential roles for soil health and microbial structure. We have investigated the effect of an anthropogenic contamination gradient on the bacterial community of the keystone ecological species Lumbricus rubellus through utilizing 16S rRNA pyrosequencing for the first time to establish the microbiome of the host and surrounding soil. The earthworm-associated microbiome differs from the surrounding environment which appears to be a result of both filtering and stimulation likely linked to the altered environment associated with the gut micro-habitat (neutral pH, anoxia and increased carbon substrates). We identified a core earthworm community comprising Proteobacteria (∼50%) and Actinobacteria (∼30%), with lower abundances of Bacteroidetes (∼6%) and Acidobacteria (∼3%). In addition to the known earthworm symbiont (Verminephrobacter sp.), we identified a potential host-associated Gammaproteobacteria species (Serratia sp.) that was absent from soil yet observed in most earthworms. Although a distinct bacterial community defines these earthworms, clear family- and species-level modification were observed along an arsenic and iron contamination gradient. Several taxa observed in uncontaminated control microbiomes are suppressed by metal/metalloid field exposure, including eradication of the hereto ubiquitously associated Verminephrobacter symbiont, which raises implications to its functional role in the earthworm microbiome.


Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges.
In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal therapeutic design.


Obstructive sleep apnea syndrome and fatty liver: association or causal link?
Obstructive sleep apnea (OSA) is a complex disorder that consists of upper airway obstruction, chronic intermittent hypoxia and sleep fragmentation. OSA is well known to be associated with hypoxia, insulin resistance and glucose intolerance, and these factors can occur in the presence or absence of obesity and metabolic syndrome. Although it is well established that insulin resistance, glucose intolerance and obesity occur frequently with non-alcoholic fatty liver disease (NAFLD), it is now becoming apparent that hypoxia might also be important in the development of NAFLD, and it is recognized that there is increased risk of NAFLD with OSA. This review discusses the association between OSA, NAFLD and cardiovascular disease, and describes the potential role of hypoxia in the development of NAFLD with OSA.


Serum Neurofilament Light Chain Levels are Associated with Lower Thalamic Perfusion in Multiple Sclerosis.
Both perfusion-weighted imaging (PWI) measures and serum neurofilament light (sNfL) chain levels have been independently associated with disability in multiple sclerosis (MS) patients. This study aimed to determine whether these measures are correlated to each other or independently describe different MS processes. For this purpose, 3T MRI dynamic susceptibility contrast (DSC)-PWI and single-molecule assay (Simoa)-based sNfL methods were utilized when investigating 86 MS patients. The perfusion measures of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were derived for the normal-appearing whole brain (NAWB), the normal-appearing white matter (NAWM), the gray matter (GM), the deep GM (DGM), and the thalamus. The normalized CBV and CBF (nCBV and nCBV) were calculated by dividing by the corresponding NAWM measure. Age- and sex-adjusted linear regression models were used to determine associations between the DSC-PWI and sNfL results. False discovery rate (FDR)-adjusted p-values < 0.05 were considered statistically significant. A greater age and thalamic MTT were independently associated with higher sNfL levels (p < 0.001 and p = 0.011) and explained 36.9% of sNfL level variance. NAWM MTT association with sNfL levels did not survive the FDR correction. In similar models, a lower thalamic nCBF and nCBV were both associated with greater sNfL levels (p < 0.001 and p = 0.022), explaining 37.8% and 44.7% of the variance, respectively. In conclusion, higher sNfL levels were associated with lower thalamic perfusion.


Feasibility and preliminary results of intensive chemotherapy and extensive irradiation in selected patients with limited small-cell lung carcinoma--results of three consecutive phase II programs.
We report the results of three consecutive programs combining initial intensive chemotherapy and radiotherapy in the treatment of patients with limited small-cell lung cancer (SCLC). The objective was to test the feasibility and the effect of high-dose chemotherapy and three thoracic irradiation programs on survival and patterns of relapse. Forty-two patients with limited SCLC were enrolled. All patients received high-dose chemotherapy (vindesine, etoposide, doxorubicin, cisplatin and cyclophosphamide or ifosfamide). In the SC 84 program, chest and brain radiotherapy was delivered during each course of chemotherapy, with a complementary irradiation after chemotherapy. In the SC 86 and SC 92 programs, patients received chemotherapy followed by thoracic irradiation and prophylactic brain and spinal axis radiotherapy. At the end of treatment, 40 patients (95%) were in complete response. During chemotherapy, high levels of toxicity were noted. All patients had grade IV hematological toxicities. The extra-hematological toxicities were digestive (grade III: 21%; grade IV: 7%) and hepatic (grades III and IV: 14%). During irradiation, patients presented digestive, pulmonary and hematological toxicities. Five patients developed late toxicities and a second malignancy was observed in 4 patients. The 2- and 5-year survival rates for all patients were 51% and 27%, respectively. Despite the marked toxicity of the initial intensive chemotherapy, the treatments are tolerable and effective in the control of extra-thoracic micrometastases, whereas they are less effective for thoracic primary tumor.


Diode-laser-based near-resonantly enhanced flow visualization in shock tunnels.
Two new near-resonantly enhanced flow visualization techniques suitable for hypersonic low-density flows in shock or arc tunnels have been developed using seeded lithium (Li) metal as the refractivity-enhancing species. Two semiconductor lasers, single-longitudinal-mode and multimode, are compared with respect to their suitability as light sources for the technique. Transient wake-flow structures around a cylinder and a model of a planetary entry vehicle are visualized to demonstrate the capabilities of this comparatively inexpensive and simple visualization system. The images show flow features which are undetectable with conventional schlieren, shadowgraph, or interferometry techniques. Furthermore, the effect of density inhomogeneities along the line-of-sight outside the region of interest can be reduced by enhancing the refractivity only in selected parts of the flowfield.


Aberration coefficients and unusual coordinates for specifying rays.
The aberration coefficients of Buchdahl have been used almost exclusively in situations where rays are specified by their points of intersection with a pair of planes in the object space of the system. A simple method is presented in this paper whereby rays may be specified by their points of intersection with a pair of not necessarily plane surfaces situated in quite distinct parts of the system. The manner in which existing schemes for computing the aberration coefficients must be modified in order to accommodate the new coordinates is considered in detail. They stem basically from the need to reinterpret the intermediate coefficients appearing in the iteration equations and include modifications to the identities between the coefficients. Three examples of the new coordinates are discussed, namely: the case where the object surface is a surface of revolution about the optic axis, and the cases where rays are specified by their points of intersection with the (physical) aperture stop of the system (aperture oordinates) or with an ideal spherical wave surface in the image space of the system (W(o) coordinates).


The Role of Attention-Deficit/hyperactivity Disorder in the Association between Verbal Ability and Conduct Disorder.
Although there is clear evidence that low verbal ability is a risk factor for conduct disorder (CD), some researchers have questioned whether this association is due to the common comorbidity between attention-deficit/hyperactivity disorder (ADHD) and CD. The present study examined the association among verbal ability, ADHD, and CD in a genetically informative sample in order to examine the role of genes and/or environmental influences shared in common with ADHD on the covariation between verbal ability and CD. Participants were 2744 adolescents from the Center for Antisocial Drug Dependence (CADD), and included 360 monozygotic (MZ) female twin pairs, 221 dizygotic (DZ) female twin pairs, 297 MZ male twin pairs, 220 DZ male twin pairs, and 274 opposite-sex DZ twin pairs. The Diagnostic Interview Schedule for Children (DISC-IV) was used to assess lifetime symptoms of ADHD and CD. Verbal ability was assessed via the Vocabulary subtest of the Wechsler Adult Intelligence Scale III (WAIS-III) for individuals over the age of 16 and the Vocabulary subtest of the Wechsler Intelligence Scale for Children III (WISC-III) for individuals under the age of 16. There was a small but significant negative covariance between verbal ability and CD and between verbal ability and ADHD. Results also suggest that the covariation between verbal ability and CD is due to influences shared in common with ADHD.


Printing the Future-Updates in 3D Printing for Surgical Applications.
Three-dimensional (3D) printing is based on additive technology in which layers of materials are gradually placed to create 3D objects. The world of 3D printing is a rapidly evolving field in the medical industry as well as in most sectors of our lives. In this report we present current technological possibilities for 3D printing in the surgical field. There are different 3D printing modalities and much confusion among clinicians regarding the differences between them. Three-dimensional printing technologies can be classified based on the basic material used: solid, liquid, and powder. We describe the main printing methods from each modality and present their advantages while focusing on their applications in different fields of surgery, starting from 3D printing of models for preoperative planning up to patient-specific implants (PSI). We present the workflow of 3D printing for the different applications and our experience in 3D printing surgical guides as well as PSI. We include examples of 3D planning as well as clinical and radiological imaging of cases. Three-dimensional printing of models for preoperative planning enhances the 3D perception of the planned operation and allows for preadaptation of surgical instruments, thus shortening operation duration and improving precision. Three-dimensional printed PSI allow for accurate reconstruction of anatomic relations as well as efficiently restoring function. The application of PSI is expanding rapidly, and we will see many more innovative treatment modalities in the near future based on this technology.


High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin.
The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20⁺ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates.


Cystic echinococcosis in Spain: current situation and relevance for other endemic areas in Europe.
Cystic echinococcosis (CE) remains an important health problem in many regions of the world, both where no control measures have been implemented, and where control programs have been incompletely successful with ensuing re-emergence of the disease. In Spain, official data on CE show an increase in the proportion of intermediate hosts with CE during the last few years, and autochthonous pediatric patients have been reported, a sign of active local transmission of disease. A similar picture emerges from data reported to the European Food Safety Authority by other European countries. Nevertheless, several crucial aspects related to CE that would help better understand and control the disease have not been tackled appropriately, in particular the emergence of infection in specific geographical areas. In this respect, while some data are missing, other data are conflicting because they come from different databases. We review the current situation of CE in Spain compared with areas in which similar problems in the CE field exist, and offer recommendations on how to overcome those limitations. Specifically, we believe that the introduction of national registries for CE with online data entry, following the example set by the European Registry for Alveolar Echinococcosis, would help streamline data collection on CE by eliminating the need for evaluating and integrating data from multiple regions, by avoiding duplication of data from patients who access several different health facilities over time, and by providing much needed clinical and epidemiological data that are currently accessible only to clinicians.


Exploratory Graph Analysis of the Strengths and Difficulties Questionnaire for Aboriginal and/or Torres Strait Islander Children.
In Australia, one of the most frequently used measures for assessing social and emotional well-being (SEWB) of Aboriginal and/or Torres Strait Islander children is the Strengths and Difficulties Questionnaire (SDQ). Previous studies on state-level validations have indicated the problems associated with the original five-factor SDQ structure, especially in the dimension of Peer Problems. The aim of this study was to use a novel psychometric methodology, namely Exploratory Graph Analysis (EGA), to evaluate the dimensionality of caregiver-informant SDQ version 4-10 years at a national level in Australia. Data for this study were retrospectively collected from two independent longitudinal studies: the Longitudinal Study of Indigenous Children (LSIC) and South Australian Aboriginal Birth Cohort (SAABC). The caregiver-informed SDQ version 4-10 years was applied across several study waves, including more than 4,000 responses. To conduct EGA, Gaussian graphical models (GGMs) were estimated using the Least Absolute Shrinkage and Selection Operator. About 2,500 bootstrap samples were also employed to investigate dimensions and item stability. The findings indicated robust evidence against the construct validity of the original five-factor SDQ structure. Future studies should conduct a direct external validation of the findings with Aboriginal and/or Torres Strait Islander parents/carers and community groups to develop the guidelines for future use of the instrument among Aboriginal and/or Torres Strait Islander children in Australia.


Systematic review of parameters of stimulation, clinical trial design characteristics, and motor outcomes in non-invasive brain stimulation in stroke.
Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation are two powerful non-invasive neuromodulatory therapies that have the potential to alter and evaluate the integrity of the corticospinal tract. Moreover, recent evidence has shown that brain stimulation might be beneficial in stroke recovery. Therefore, investigating and investing in innovative therapies that may improve neurorehabilitative stroke recovery are next steps in research and development. Participants/Materials and Methods: This article presents an up-to-date systematic review of the treatment effects of rTMS and tDCS on motor function. A literary search was conducted, utilizing search terms "stroke" and "transcranial stimulation." Items were excluded if they failed to: (1) include stroke patients, (2) study motor outcomes, or (3) include rTMS/tDCS as treatments. Other exclusions included: (1) reviews, editorials, and letters, (2) animal or pediatric populations, (3) case reports or sample sizes ≤2 patients, and (4) primary outcomes of dysphagia, dysarthria, neglect, or swallowing. Investigation of PubMed English Database prior to 01/01/2012 produced 695 applicable results. Studies were excluded based on the aforementioned criteria, resulting in 50 remaining studies. They included 1314 participants (1282 stroke patients and 32 healthy subjects) evaluated by motor function pre- and post-tDCS or rTMS. Heterogeneity among studies' motor assessments was high and could not be accounted for by individual comparison. Pooled effect sizes for the impact of post-treatment improvement revealed consistently demonstrable improvements after tDCS and rTMS therapeutic stimulation. Most studies provided limited follow-up for long-term effects. It is apparent from the available studies that non-invasive stimulation may enhance motor recovery and may lead to clinically meaningful functional improvements in the stroke population. Only mild to no adverse events have been reported. Though results have been positive results, the large heterogeneity across articles precludes firm conclusions.


Wastewater for agriculture: A reuse-oriented planning model and its application in peri-urban China.
The benefits of Integrated Water Resources Management (IWRM) are widely known but its recommendations remain thinly implemented. Designing wastewater treatment plants for reuse in irrigation is a particularly underutilized IWRM opportunity that could potentially increase agricultural yields, conserve surface water, offset chemical fertilizer demand, and reduce the costs of wastewater treatment by eliminating nutrient removal processes. This paper presents a novel planning model, consisting of a reuse-centric performance assessment and optimization model to help design wastewater treatment plants for reuse in agriculture. The performance assessment and optimization model are described, and their coupled application is demonstrated in the peri-urban district of Pixian, China. Based on the results of the performance assessment, two reuse scenarios are evaluated: wastewater to supplement business as usual (BAU) irrigation, and wastewater to replace BAU irrigation. The results indicate that wastewater supplementation could increase profits by $20 million (M) annually; alternatively, wastewater replacement could conserve 35Mm(3) of water in local rivers each year.


Whole proteome identification of plant candidate G-protein coupled receptors in Arabidopsis, rice, and poplar: computational prediction and in-vivo protein coupling.
The classic paradigm of heterotrimeric G-protein signaling describes a heptahelical, membrane-spanning G-protein coupled receptor that physically interacts with an intracellular G alpha subunit of the G-protein heterotrimer to transduce signals. G-protein coupled receptors comprise the largest protein superfamily in metazoa and are physiologically important as they sense highly diverse stimuli and play key roles in human disease. The heterotrimeric G-protein signaling mechanism is conserved across metazoa, and also readily identifiable in plants, but the low sequence conservation of G-protein coupled receptors hampers the identification of novel ones. Using diverse computational methods, we performed whole-proteome analyses of the three dominant model plant species, the herbaceous dicot Arabidopsis thaliana (mouse-eared cress), the monocot Oryza sativa (rice), and the woody dicot Populus trichocarpa (poplar), to identify plant protein sequences most likely to be GPCRs. Our stringent bioinformatic pipeline allowed the high confidence identification of candidate G-protein coupled receptors within the Arabidopsis, Oryza, and Populus proteomes. We extended these computational results through actual wet-bench experiments where we tested over half of our highest ranking Arabidopsis candidate G-protein coupled receptors for the ability to physically couple with GPA1, the sole G alpha in Arabidopsis. We found that seven out of eight tested candidate G-protein coupled receptors do in fact interact with GPA1. We show through G-protein coupled receptor classification and molecular evolutionary analyses that both individual G-protein coupled receptor candidates and candidate G-protein coupled receptor families are conserved across plant species and that, in some cases, this conservation extends to metazoans. Our computational and wet-bench results provide the first step toward understanding the diversity, conservation, and functional roles of plant candidate G-protein coupled receptors.


Increased free water in the substantia nigra of Parkinson's disease: a single-site and multi-site study.
Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson's disease. It is the case, however, that partial volume effects from free water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free water is elevated in the substantia nigra for Parkinson's disease compared with control subjects. This hypothesis was tested between large cohorts of Parkinson's disease and control participants in a single-site study and validated against a multisite study using multiple scanners. The fractional volume of free water was increased in the posterior region of the substantia nigra in Parkinson's disease compared with control subjects in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water-corrected fractional anisotropy or free-water-corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson's disease, and this was evidenced across both single-site and multi-site cohorts.


Tuning major gene variants conditioning human behavior: the anachronism of ADHD.
New findings suggest that attention deficit and hyperactivity disorder (ADHD) is the most common behavioral variant associated with a mental condition. ADHD prevalence reaches figures of 18% in populations worldwide. Furthermore, genetic variants conferring susceptibility to develop ADHD are not rare but very frequent and eventually totally fixed in some populations. These patterns of evolution can be associated with the fact that this behavioral trait had provided selective advantage. However, this behavioral trait is now under scrutiny because of new emerging social necessities. Recent molecular and clinical evidence supports Thom Hartmann's Hunter-Farmer theory, reaffirming that ADHD might be an anachronic behavioral trait.


Assessing the factor structure and measurement invariance of the eating attitude test (EAT-26) across language and BMI in young Arab women.
The objective of the study was to determine the factorial structure and test the measurement invariance of the EAT-26 in a large probability sample of young female university students in Qatar (n = 2692), a Muslim country in the Middle East. The maximum number of factors was derived based on results from initial exploratory factor analysis (EFA) in the first-half of the randomly split sample (Sample 1). A subsequent EFA and Exploratory Structural Equation Models (ESEM) were conducted to identify the number of valid factors. A five-factor model with 19 items was identified as the optimal factor structure. This structure was further replicated using ESEM in the second-half of the sample (Sample 2). Multi-group Confirmatory Factor Analyses (CFAs) were conducted at this stage and their fit was evaluated with and without further sub-grouping by language (Arabic and English) and BMI (underweight, normal weight, and overweight/obese). Finally, measurement invariance tests were conducted in the entire sample assessing equivalence across language and BMI within the final five-factor model. The five-factor structure of the new EAT-19 [fear of getting fat (FGF), eating-related control (ERC), food preoccupation (FP), vomiting-purging behavior (VPB), and social pressure to gain weight (SP)] provided the best fit: CFI = 0.976, TLI = 0.952, RMSEA = 0.045 (90%CI 0.039-0.051), SRMR = 0.018, CD =1.000. CFAs supported metric invariance for language and for BMI. Language and BMI-based population heterogeneity comparisons provided modest and small-to-moderate evidence for differential factor means, respectively. Although the five-factor model of the EAT-19 demonstrated good item characteristics and reliability in this young female population, the lack of scalar invariance across language and BMI-categories pose measurement challenges for use of this scale for screening purposes. Future studies should develop culture- and BMI-specific cut-offs when using the EAT as a screening instrument for disordered eating in non-clinical populations.


Early-stage memory loss support groups: outcomes from a randomized controlled clinical trial.
This article describes results of a randomized controlled trial comparing a time-limited early-stage memory loss (ESML) support group program conducted by a local Alzheimer's Association chapter to a wait-list (WL) control condition. One hundred and forty-two dyads were randomized in blocks to ESML (n = 96) or WL (n = 46). Mean age of participants was 74.9 years, and mean Mini-Mental State Examination was 23.4. The primary outcome was participant's quality of life; secondary outcomes included mood, family communication, and perceived stress. On the intent-to-treat (ITT) pre-post analysis, significant differences were seen in participant quality of life (p < .001), depression (p < .01), and family communication (p < .05). Within the care partner groups, there was no significant difference between ESML and WL in the ITT analysis. A post hoc exploratory examination of changes that were associated with improved quality of life in ESML participants revealed significant reductions of depressive symptoms and behavior problems (p < .05), improved family communication (p < .05), self-efficacy (p < .01), Medical Outcomes Study short form (SF-36) role-emotional (p < .05), SF-36 social functioning (p < .05), and SF-36 mental health components (p < .01) in improvers. These results support the efficacy of ESML support groups for individuals with dementia.


Recent advances in chemical genomics.
Chemical genomics, which utilizes specially designed small chemical compounds early in the discovery phase of new drugs to explore the life science at various levels, can address biological questions that are not amenable to genetic manipulation or functional genomics/proteomics approaches. Following the development of HT phenotypic assays and DNA expression analysis, the integration of cell-based assays with activity / affinity-based approaches allows us to interrogate the cells by analyzing phenotypic alterations, changes of transcript signature or detecting the differences in protein expression levels. Furthermore, activity / affinity-based techniques directly provide a druggable subset of gene products, which interact with small molecules, greatly reducing the complexity of analyzing the proteome. In this paper, we give an account of the recent advances (approaches and strategies) in the field of chemical genomics, and discuss how these approaches enable the investigator to obtain a novel therapeutically relevant target as well as drug candidates acting on them in a target-specific manner. This novel post-genomic discovery strategy, where target identification/ validation is carried out by interactions with small molecules, could significantly reduce the time-scale for early drug discovery, and increase the success rate of finding novel, druggable targets, as well as more specific drug candidates.


Selection of long oligonucleotides for gene expression microarrays using weighted rank-sum strategy.
The design of long oligonucleotides for spotted DNA microarrays requires detailed attention to ensure their optimal performance in the hybridization process. The main challenge is to select an optimal oligonucleotide element that represents each genetic locus/gene in the genome and is unique, devoid of internal structures and repetitive sequences and its Tm is uniform with all other elements on the microarray. Currently, all of the publicly available programs for DNA long oligonucleotide microarray selection utilize various combinations of cutoffs in which each parameter (uniqueness, Tm, and secondary structure) is evaluated and filtered individually. The use of the cutoffs can, however, lead to information loss and to selection of suboptimal oligonucleotides, especially for genomes with extreme distribution of the GC content, a large proportion of repetitive sequences or the presence of large gene families with highly homologous members. Here we present the program OligoRankPick which is using a weighted rank-based strategy to select microarray oligonucleotide elements via an integer weighted linear function. This approach optimizes the selection criteria (weight score) for each gene individually, accommodating variable properties of the DNA sequence along the genome. The designed algorithm was tested using three microbial genomes Escherichia coli, Saccharomyces cerevisiae and the human malaria parasite species Plasmodium falciparum. In comparison to other published algorithms OligoRankPick provides significant improvements in oligonucleotide design for all three genomes with the most significant improvements observed in the microarray design for P. falciparum whose genome is characterized by large fluctuations of GC content, and abundant gene duplications. OligoRankPick is an efficient tool for the design of long oligonucleotide DNA microarrays which does not rely on direct oligonucleotide exclusion by parameter cutoffs but instead optimizes all parameters in context of each other. The weighted rank-sum strategy utilized by this algorithm provides high flexibility of oligonucleotide selection which accommodates extreme variability of DNA sequence properties along genomes of many organisms.


Modification of a pivot bearing system on a compact centrifugal pump.
The pivot bearing centrifugal blood pump was developed as a long-term centrifugal ventricular assist device (VAD) as well as a cardiopulmonary bypass pump. This pivot bearing supported centrifugal pump with an eccentric port (CIE) incorporates a seal-less design with a blood stagnation-free structure. This pump can provide flows of 12 L/min against 650 mm Hg total pressure head at 3,600 rpm, and in a CPB condition 5 L/min against 350 mm Hg total pressure head at 2,600 rpm. Very recently, the pivot bearing system was modified to obtain a stable and smooth spinning movement. The material of the female pivot was changed from ceramic to polyethylene. Three kinds of bearings were tested simultaneously with bovine blood in two types of in vitro circuits to determine the blood damage from the bearings. Pressure differences across the pump (total head pressure, delta P) of 140 mm Hg (n = 12) and 330 mm Hg (n = 12) were examined. The normalized index of hemolysis (NIH) was slightly higher in a ball bearing (BB) pump than in a polyethylene bearing (PB) pump and statistically higher than the BioMedicus Pump (BP-80) on delta P of 140 mm Hg. When the delta P was at 330 mm Hg, a comparison between the three types of pumps revealed no difference in NIH. In addition, the primary vane of the impeller was redesigned to obtain an atraumatic structure. In the second study (n = 14), there was no difference in the NIH between BP-80 and the current model when the delta P was 300 mm Hg (0.019 +/- 0.002 vs. 0.027 +/- 0.006, p = 0.3) and/or when the delta P was 100 mm Hg (0.0008 +/- 0.0001 vs. 0.0014 +/- 0.0002, p = 0.07). The modified pivot bearing had an improved spinning condition and no change in hemolysis. A proper selection of pivot bearing materials is important to develop an atraumatic centrifugal pump. The modification of the bearing system and redesign of the vane enabled a compact centrifugal pump to become a reality.


Learning performance is associated with social preferences in a group-living fish.
Many animals live in groups yet grouping tendencies and preferences for groups of different sizes vary considerably between individuals. This variation reflects, at least in part, differences in how individuals evaluate and perceive their physical surroundings and their social environment. While such differences are likely related to individual variation in cognition, there have been few studies that have directly investigated how cognitive abilities are linked to individual grouping decisions. Therefore, in this study we assessed whether performance on a foraging-based reversal learning task is related to grouping preferences (a group of three fish versus a single fish) in a group-living cichlid fish, Neolamprologus pulcher. While most fish preferred to associate with the group over a single fish, individuals that completed the reversal learning task the quickest were the least interested in the group under elevated predation risk. In addition, fish that quickly completed the reversal learning task also adjusted their grouping preferences the most when predation risk increased. This result suggests that the observed relationship between learning performance and grouping decisions may be linked to individual differences in behavioural flexibility. Overall, our results offer valuable insight into the potential factors that underlie inter-individual variation in grouping decisions.


Condition-specific RNA editing in the coral symbiont Symbiodinium microadriaticum.
RNA editing is a rare post-transcriptional event that provides cells with an additional level of gene expression regulation. It has been implicated in various processes including adaptation, viral defence and RNA interference; however, its potential role as a mechanism in acclimatization has just recently been recognised. Here, we show that RNA editing occurs in 1.6% of all nuclear-encoded genes of Symbiodinium microadriaticum, a dinoflagellate symbiont of reef-building corals. All base-substitution edit types were present, and statistically significant motifs were associated with three edit types. Strikingly, a subset of genes exhibited condition-specific editing patterns in response to different stressors that resulted in significant increases of non-synonymous changes. We posit that this previously unrecognised mechanism extends this organism's capability to respond to stress beyond what is encoded by the genome. This in turn may provide further acclimatization capacity to these organisms, and by extension, their coral hosts.


Comparison of changes in the dental transverse and sagittal planes between patients treated with self-ligating and with conventional brackets.
Several advantages have been established regarding the efficiency of self-ligating brackets (SL). In spite of some controversy surrounding this question in the literature, clinical results confirm that "arch development" requires fewer extractions. The objective of this study was to compare changes in the transverse and sagittal planes in patients treated with conventional ligating brackets (CL)as well as in patients treated with SL brackets and oversized arches. A sample was selected from a pool of 300 consecutive cases treated by a single clinician: 51 patients with SL brackets and oversized wires, and 55 with CL brackets. These two groups were compared with a control group of 20 patients. All plaster models were scanned and dental landmarks were measured to identify changes from commencement (T0) to conclusion (T1) of treatment. Lateral cephalograms were analyzed for changes in the lower incisor (IMPA) and the first lower molar distal angulation (MAng). Intraoperator reliability was tested with linear regression analysis. To assure all groups were comparable at T0, an ANOVA test with a 95%confidence interval (CI) was performed for all values. To assess changes from T0 to T1 in all groups, a Student's t-test with 95% CI was used. Finally, results from the three groups were compared using an ANOVA-test (95% CI) and a post-hoc test. Increases in all the transverse variables were recorded in the two groups treated (SL and CL), except for the lower intercanine distance in the SL group. IMPA difference from T0 to T1 was higher in the CL group, and molar distal angulation (MAng) took place in the SL group. Self-ligating brackets with oversized arches and conventional ligating brackets showed increases in all variables in the transverse plane, except for the SL group at the mandibular intercanine distance. In comparison with the CL group, fewer different IMPA values were observed in the SL group, in which distal molar angulation occurred.


Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis.
Over the last 10 years, interest in pediatric tuberculosis (TB) has increased dramatically, together with increased funding and research. We have a better understanding of the burden of childhood TB as well as a better idea of how to diagnose it. Our appreciation of pathophysiology is improved and with it investigators are beginning to consider pediatric TB as a heterogeneous entity, with different types and severity of disease being treated in different ways. There have been advances in how to treat both TB infection and TB disease caused by both drug-susceptible as well as drug-resistant organisms. Two completely novel drugs, bedaquiline and delamanid, have been developed, in addition to the use of older drugs that have been re-purposed. New regimens are being evaluated that have the potential to shorten treatment. Many of these drugs and regimens have first been investigated in adults with children an afterthought, but increasingly children are being considered at the outset and, in some instances studies are only conducted in children where pediatric-specific issues exist.


The founding of the medical school in Singapore in 1905.
This article traces briefly the origins of medical education in the early years of the Straits Settlements (Singapore, Penang and Malacca), which culminated in the founding of Medical School in Singapore in 1905. The first attempt was made in the early 19th century, when boys were recruited from local schools as Medical Apprentices to be trained as "assistant doctors". They were to assist the British doctors and doctors from India in running the medical services. This scheme was not successful. There are 3 landmark years in the evolution of medical education in the Straits Settlements, namely 1852, 1867 and 1904. In 1852, the Governor, to relieve the shortage of staff in the Medical Department, instructed the Principal Civil Medical Officer to organise a proper course of training for Medical Apprentices and to establish a local Medical Service. This scheme was also unsuccessful and the Straits Settlements continued to rely on doctors recruited from India. In 1867, the Straits Settlements were transferred from the India Office to the Colonial Office and became a Crown Colony. The Indian Government requested that all its doctors be sent back. This would have led to the collapse of the Straits Settlements Medical Service. As a stop-gap measure, the Governor offered the Indian doctors appointment in the new Straits Settlements Medical Service, and at the same time arranged with the Madras Government for boys from the Straits Settlements to be trained in its Medical Colleges. The first 2 boys were sent in 1869. In 1889, the Principal Civil Medical Officer proposed to the Governor that a Medical School should be founded in Singapore, but not enough candidates passed the preliminary entrance examination. The plan was shelved and boys continued to be sent to Madras for training. In 1902, the Committee on English Education proposed that a Medical School should be started in Singapore, but senior British doctors opposed this. On 8 September 1904, Mr Tan Jiak Kim and other local community leaders petitioned the Governor to start a Medical School, raised enough funds to establish the School and the Straits and Federated Malay States Government Medical School (predecessor of the King Edward VII College of Medicine, and the Faculties of Medicine, University of Singapore and University of Malaya) was founded on 3 July 1905.


A Review of the Cognitive Effects Observed in Humans Following Acute Supplementation with Flavonoids, and Their Associated Mechanisms of Action.
Flavonoids are polyphenolic compounds found in varying concentrations in many plant-based foods. Recent studies suggest that flavonoids can be beneficial to both cognitive and physiological health. Long term flavonoid supplementation over a period of weeks or months has been extensively investigated and reviewed, particularly with respect to cognitive ageing and neurodegenerative disease. Significantly less focus has been directed towards the short term effects of single doses of flavonoids on cognition. Here, we review 21 such studies with particular emphasis on the subclass and dose of flavonoids administered, the cognitive domains affected by flavonoid supplementation, and the effect size of the response. The emerging evidence suggests that flavonoids may be beneficial to attention, working memory, and psychomotor processing speed in a general population. Episodic memory effects are less well defined and may be restricted to child or older adult populations. The evidence also points towards a dose-dependent effect of flavonoids, but the physiological mechanisms of action remain unclear. Overall, there is encouraging evidence that flavonoid supplementation can benefit cognitive outcomes within an acute time frame of 0-6 h. But larger studies, combining cognitive and physiological measures, are needed to strengthen the evidence base.


Multiple bowel perforations requiring extensive bowel resection and hysterectomy after microwave endometrial ablation.
Heavy menstrual bleeding, or menorrhagia, is a primary cause of morbidity in women. Herein, we present the case of a 41-year-old woman who underwent day-surgery endometrial microwave ablation because of dysfunctional uterine bleeding. She had undergone previous laparoscopic sterilization, and had no other risk factors except for a retroverted uterus. The procedure was performed without any documented difficulties. The patient was readmitted the following day with clinical signs of acute abdomen. Emergency laparotomy revealed a large perforation on the anterior uterine wall, full-thickness burns in the distal ileum, and multiple ischemic areas in the ileum, cecum, and ascending colon secondary to microwave burns. A right hemicolectomy was required, with extended ileal resection and subtotal hysterectomy with ovarian conservation. Although microwave endometrial therapy seems to offer many advantages, in particular in terms of efficiency and technique, complications occur, and extensive safety measures must be implemented to prevent adverse effects such as occurred in this patient.


Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results from the Canary PASS Cohort.
Active surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort. Participants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed. At diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent radical prostatectomy after initial surveillance, the adjusted risk of adverse pathology was similar (HR=1.26; p=0.4). Biochemical recurrence within 3 years of treatment for GG2 and GG1 patients was 6% for both groups. In patients on AS, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after radical prostatectomy and short-term biochemical recurrence after definitive treatment were similar between GG2 and GG1.


Diagnosis and treatment of slipped capital femoral epiphysis.
Slipped capital femoral epiphysis remains a diagnostic problem despite numerous papers written on the subject. The most important factor in the diagnosis of slipped capital femoral epiphysis is suspicion by the practitioner. The history, physical examination, and radiographic imaging are important in the confirmation of the diagnosis. Imaging is the topic of 1998 with advances in the areas of ultrasound. Ultrasound may be better in experienced hands than plain radiography in the diagnosis of slipped capital femoral epiphysis. Magnetic resonance imaging is used for diagnosis of slipped capital femoral epiphysis and in the assessment of pre-slips. The magnetic resonance image can be oriented to a plane orthoganol to the plane of the physis to assess the width of the physis and to detect edema in the area of the physis.


Effect of resveratrol supplementation on cognitive performance and mood in adults: a systematic literature review and meta-analysis of randomized controlled trials.
The aim of this systematic review was to evaluate clinical trial data regarding the effect of resveratrol supplementation on cognitive performance and mood in populations that are healthy and in the clinical setting. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review of randomized controlled trials was conducted. A meta-analysis was also conducted to determine treatment effect on the following cognitive domains and mental processes: processing speed, number facility, memory, and mood. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias tool. Quality of the body of evidence was assessed by evidence for each outcome related to cognitive function for which data was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Ten studies were included. Three studies found resveratrol supplementation significantly improved some measures of cognitive performance, 2 reported mixed findings, and 5 found no effect. When data were pooled, resveratrol supplementation had a significant effect on delayed recognition (standardized mean difference [SMD], 0.39; 95% confidence interval [CI], 0.08-0.70; I2 = 0%; P = 0.01; n = 3 studies; n = 166 participants) and negative mood (SMD, -0.18; 95%CI, -0.31 to -0.05; I2 = 0%; P = 0.006; n = 3 studies; n = 163 participants). Included studies generally had low risk of bias and were of moderate or high quality. The results of this review indicate that resveratrol supplementation might improve select measures of cognitive performance; however, the current literature is inconsistent and limited.


The Genetics of Infertility: Current Status of the Field.
Infertility is a relatively common health condition, affecting nearly 7% of all couples. Clinically, it is a highly heterogeneous pathology with a complex etiology that includes environmental and genetic factors. It has been estimated that nearly 50% of infertility cases are due to genetic defects. Hundreds of studies with animal knockout models convincingly showed infertility to be caused by gene defects, single or multiple. However, despite enormous efforts, progress in translating basic research findings into clinical studies has been challenging. The genetic causes remain unexplained for the vast majority of male or female infertility patients. A particular difficulty is the huge number of candidate genes to be studied; there are more than 2,300 genes expressed in the testis alone, and hundreds of those genes influence reproductive function in humans and could contribute to male infertility. At present, there are only a handful of genes or genetic defects that have been shown to cause, or to be strongly associated with, primary infertility. Yet, with completion of the human genome and progress in personalized medicine, the situation is rapidly changing. Indeed, there are 10-15 new gene tests, on average, being added to the clinical genetic testing list annually.


Differentially interconnected networks of GABAergic interneurons in the visual cortex of the cat.
Networks of GABAergic neurons have been implicated in neuronal population synchronization. To define the extent of cellular interconnections, we determined the effect, number, and subcellular distribution of synapses between putative GABAergic neurons in layers II-IV of the cat visual cortex using paired intracellular recordings in vitro followed by correlated light and electron microscopy. All neurons having interneuronal electrophysiological properties were classified by their postsynaptic target profile and were identified as basket (BC; n = 6), dendrite-targeting (DTC; n = 1), and double bouquet (DBC; n = 2) cells. In four out of five anatomically fully recovered and reconstructed cell pairs, synaptic connections were found to be reciprocal. Generally BCs established synaptic junctions closer (21 +/- 20 micron) to postsynaptic somata than did DBCs (43 +/- 19 micron; p < 0.01). The unitary number of synapses (n values, 10, 7, and 20) in each of three BC-to-BC pairs was higher than that in three BC-to-DBC (n values, 1, 2, and 2) and three DBC-to-BC (n values, 1, 4, and 4) connections (p < 0.05). A BC innervated a DTC through two synaptic junctions. Unitary postsynaptic effects mediated by five BCs could be recorded in two BCs, two DBCs, and a DTC. The BCs elicited short-duration fast IPSPs, similar to those mediated by GABAA receptors. At a membrane potential of -55.0 +/- 6.4 mV, unitary IPSPs (n = 5) had a mean amplitude of 919 +/- 863 microV. Postsynaptic response failures were absent when an IPSP was mediated by several release sites. Thus, distinct GABAergic interneurons form reciprocally interconnected networks. The strength of innervation and the proximal placement of synapses suggest a prominent role for BCs in governing the activity of intracortical GABAergic networks in layers II-IV.


Intravenous RMP-7 selectively increases uptake of carboplatin into rat brain tumors.
Rats implanted with RG-2 gliomas were administered i.v. RMP-7 and [14C]carboplatin. Changes in the permeability of the blood-brain barrier to carboplatin were determined using quantitative autoradiography. i.v. infusions of RMP-7 induced an increase in the permeability of the vascular barrier within the tumor to carboplatin. Additionally, permeability of brain tissue proximal to, but clearly outside the tumor mass, was also increased. Progressively less uptake of [14C]carboplatin was observed as distance from the tumor border increased. The increases in permeability induced by RMP-7 occurred in a dose-related fashion. No increase in carboplatin level was observed in several nonbrain tissues, including sciatic nerve, retina, heart, lung, liver, kidney, and spleen. Finally, the permeabilizing effects of RMP-7 were shown to occur independent of histaminergic or hypotensive mechanisms. These data provide additional insight into the permeabilizing effects and mechanism of RMP-7 and offer additional support for the therapeutic utility of this novel compound as an adjunctive treatment for human gliomas.


Fish and long-chain n-3 polyunsaturated fatty acid intakes during pregnancy and risk of postpartum depression: a prospective study based on a large national birth cohort.
Mothers may be reluctant to receive medical treatment of postpartum depression (PPD), despite the detrimental consequences the disorder can impose on mother and child. Research on alternative methods of prevention and treatment of PPD is warranted. Previous studies have suggested that long-chain n-3 polyunsaturated fatty acids (PUFAs) might have a beneficial effect on depression. The objective was to explore the association between intake of fish and n-3 PUFAs during pregnancy and PPD in the Danish National Birth Cohort (DNBC). Exposure information from the DNBC was linked to the Danish patient and prescription registries for data on clinically identified cases of depression up to 1 y postpartum. Intake of fish and n-3 PUFAs was assessed in midpregnancy with a food-frequency questionnaire. Admission to the hospital for PPD (PPD-admission) and prescription of antidepressants (PPD-prescription) were treated as separate outcomes. A total of 54,202 women were included in the present study sample. Rates of depression were 0.3% (PPD-admission) and 1.6% (PPD-prescription). No association was observed between fish intake and risk of PPD-admission [crude odds ratio of 1.01 (95% CI: 0.52, 1.97) and adjusted odds ratio of 0.82 (95% CI: 0.42, 1.64)], whereas a higher risk of PPD-prescription was found for the lowest compared with the highest fish intake group [crude odds ratio of 1.61 (95% CI: 1.26, 2.06) and adjusted odds ratio of 1.46 (95% CI: 1.12, 1.90)]. No association was observed with respect to n-3 PUFA intake. Overall, our data from a large prospective cohort linked with high-quality registers showed little evidence to support an association between intake of fish or n-3 PUFAs and PPD.


Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081.
Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5-G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5-G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration.


Glutamine Modulates Changes in Intestinal Intraepithelial γδT-Lymphocyte Expressions in Mice With Ischemia/Reperfusion Injury.
This study investigated the effect of glutamine (GLN) on expressions of small intestinal intraepithelial lymphocyte (IEL) γδT-cell proinflammatory cytokines and apoptotic regulatory factor genes in a mouse model of hindlimb ischemia/reperfusion (IR) injury. Mice were assigned to a normal control group and three IR groups. Mice in the normal control group received no ischemia treatment, whereas IR groups had hindlimb ischemia for 90 min with subsequent 0 (IR0) or 24 h (IR24) of reperfusion. The IR0 group was sacrificed immediately after reperfusion. The IR24S group was injected with saline, and the IR24G group was given 0.75 g GLN/kg of body weight once via a tail vein before reperfusion. The IR24 groups were sacrificed 24 h after reperfusion. Small intestinal IEL γδT cells of the animals were isolated for further analysis. Results showed that IR injury resulted in lower small intestinal IEL γδT-cell percentages and higher proinflammatory cytokine messenger RNA expressions of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α by IEL γδT cells. Compared with the IR24S group, the IR24G group had a higher IEL γδT-cell percentage. Multiples of change of messenger RNA of proliferation gene expressions of the antiapoptotic Bcl-xl (B-cell lymphoma-extra large) and IL-7 receptor in the IR24G group were higher, whereas expressions of the keratinocyte growth factor and bacterial lectin regenerating islet-derived (Reg)IIIγ were lower in IEL γδT cells. Histological findings also showed that damage to the intestinal mucosa was less severe in the IR group with GLN. These results indicated that a single dose of GLN administered before reperfusion maintained small intestinal IEL γδT cell populations and reduced expressions of intestinal inflammatory cytokines, which may have consequently ameliorated the severity of IR-induced small intestinal epithelial injury.


Treatment of kraft evaporator condensate using a thermophilic submerged anaerobic membrane bioreactor.
The feasibility of using a thermophilic submerged anaerobic membrane bioreactor (SAnMBR) for kraft evaporator condensate treatment was studied at 55+/-1 degrees C over 6.5 months. Under tested organic loading rate of 1-7 kg COD/m(3) day, a soluble COD removal efficiency of 85-97% was obtained. The methane production rate was 0.35+/-0.1 L methane/g COD and the produced biogas was of excellent fuel quality with 80-90% methane. A higher membrane fouling rate was related to the presence of a larger portion of fine colloidal particles (1-10 mum). The thermophilic SAnMBR was sensitive to the presence of toxic compounds in feed and unexpected pH probe failure (leading to a higher pH). Feed toxic shock caused sludge deflocculation and thus deteriorated membrane performance. Operating the reactor as a conventional anaerobic reactor to waste some of the fine flocs in treated effluent during the start-up process was an effective strategy to reduce membrane fouling. The experimental results from this study indicate that treatment of kraft evaporator condensate is feasible in terms of COD removal and biogas production using thermophilic SAnMBRs but pre-treatment may be needed to remove toxic sulfur compounds and membrane fouling caused by the large portion of fine particles may be a challenge.


An experimental study of attention, labelling and memory in people suffering from chronic pain.
Cognitive-behavioural approaches to treatment have become an important part of the clinical management of chronic pain. More recent developments in cognitive-behavioural theory, based on recent developments in the understanding and treatment of health anxiety, have emphasized the importance of catastrophizing appraisals, which drive both attentional processes and behavioural responses, which in turn are believed to be crucial for the maintenance of chronic pain. The experiment conducted here investigated the responses of pain patients (n=39) and controls (n=71) to a behavioural task (prolonged squeezing a dynamometer). Subsequently, the impact of a cognitive task, which fully engaged participants' attention (dichotic listening) was examined. Participants were asked, firstly, to sustain an isometric muscle contraction task (squeezing); secondly, to learn an attentional demanding task (dichotic listening); thirdly, to recall the discomfort experienced in the squeezing task and lastly, to perform both squeezing and dichotic listening at the same time. The squeezing tasks were experimentally manipulated by attaching a more or less negative label ("pain tolerance test" vs. "muscle stamina and strength test"). Patients were found to be less able to sustain prolonged muscle tension than controls, but the effect was not evident once the distracting task was introduced; similar effects were found for discomfort. All participants subsequently recalled the squeezing task as being longer and associated with less discomfort than they had actually recorded it at the time. In the dichotic listening tasks, although patients detected the same number of words overall as controls did, they were less able to focus on the target channel (i.e. they detected more of the words included as distractors on the unattended channel).


Mechanical-activated digital microfluidics with gradient surface wettability.
This paper reports a simple yet effective droplet manipulation approach that can displace aqueous droplets over a long distance within the working plane. Repeated patterns with surface gradient wettability were created on a super-hydrophobic surface by laser irradiation. Aqueous droplets as small as 2 μL are moved on the patterns over a long distance under in-plane symmetric cyclic vibration. Typical droplet manipulation actions including droplet movement along a pre-determined trajectory, droplet mixing, and selective movement of multiple droplets were successfully demonstrated. Biochemical detection using this approach was demonstrated via a bicinchoninic acid (BCA) assay. This approach allows for long-distance droplet movement and simultaneous manipulation of multiple droplets without sacrificing the manipulation efficiency or increasing the cross-contamination risk. The device can be fabricated outside cleanrooms and operated without special equipment. It provides a solid technical basis for developing the next generation of affordable open channel microfluidic devices for various applications.


Porous tantalum and poly-epsilon-caprolactone biocomposites for osteochondral defect repair: preliminary studies in rabbits.
Currently, various techniques are in use for the repair of osteochondral defects, none of them being truly satisfactory and they are often two step procedures. Comorbidity due to cancellous bone harvest from the iliac crest further complicates the procedure. Our previous in vitro studies suggest that porous tantalum (TM) or poly-epsilon-caprolactone scaffolds (PCL) in combination with periosteal grafts could be used for osteochondral defect repair. In this in vivo study, cylindrical osteochondral defects were created on the medial and lateral condyles of 10 rabbits and filled with TM/periosteum or PCL/periosteum biosynthetic composites (n = 8 each). The regenerated osteochondral tissue was then analyzed histologically, and evaluated in an independent and blinded manner by five different observers using a 30-point histological score. The overall histological score for PCL/periosteum was significantly better than for TM/periosteum. However, most of the regenerates were well integrated with the surrounding bone (PCL/periosteum, n = 6.4; TM/periosteum, n = 7) along with partial restoration of the tidemark (PCL/periosteum, n = 4.4; TM/periosteum, n = 5.6). A cover of hyaline-like morphology was found after PCL/periosteum treatment (n = 4.8), yet the cartilage yields were inconsistent. In conclusion, the applied TM and PCL scaffolds promoted excellent subchondral bone regeneration. Neo-cartilage formation from periosteum supported by a scaffold was inconsistent. This is the first study to show in vivo results of both PCL and TM scaffolds for a novel approach to osteochondral defect repair.