Biphasic chemotaxis of Escherichia coli to the microbiota metabolite indole.
Bacterial chemotaxis to prominent microbiota metabolites such as indole is important in the formation of microbial communities in the gastrointestinal (GI) tract. However, the basis of chemotaxis to indole is poorly understood. Here, we exposed Escherichia coli to a range of indole concentrations and measured the dynamic responses of individual flagellar motors to determine the chemotaxis response. Below 1 mM indole, a repellent-only response was observed. At 1 mM indole and higher, a time-dependent inversion from a repellent to an attractant response was observed. The repellent and attractant responses were mediated by the Tsr and Tar chemoreceptors, respectively. Also, the flagellar motor itself mediated a repellent response independent of the receptors. Chemotaxis assays revealed that receptor-mediated adaptation to indole caused a bipartite response-wild-type cells were attracted to regions of high indole concentration if they had previously adapted to indole but were otherwise repelled. We propose that indole spatially segregates cells based on their state of adaptation to repel invaders while recruiting beneficial resident bacteria to growing microbial communities within the GI tract.


Effects of serum PSA on efficacy of tolterodine extended release with or without tamsulosin in men with LUTS, including OAB.
To evaluate the efficacy of tolterodine extended release (ER), tamsulosin, and tolterodine ER plus tamsulosin in men with symptoms of overactive bladder and benign prostatic hyperplasia stratified by prostate-specific antigen (PSA) level. We performed a post hoc analysis of data from men >or=40 years old with frequency and urgency (with or without urge urinary incontinence), postvoid residual urine volume <200 mL, maximal urinary flow rate >5 mL/s, International Prostate Symptom Score (IPSS) of >or=12, and quality-of-life score of >or=3. They had been randomized to placebo, tolterodine ER (4 mg), tamsulosin (0.4 mg), or tolterodine ER plus tamsulosin for 12 weeks. The men were stratified by the median baseline PSA level (>or=1.3 vs <1.3 ng/mL). Assessments included changes in bladder diary variables and IPSSs. The men rated the urgency level of each micturition, and the frequency-urgency sum was defined as the total of these ratings. The PSA level correlated significantly with prostate size. Men with a PSA level of >or=1.3 ng/mL receiving tolterodine ER plus tamsulosin showed significantly greater improvements in 24-hour frequency, daytime frequency, the frequency-urgency sum, total IPSS, and IPSS storage score compared with those receiving placebo. Tamsulosin significantly improved the IPSS voiding scores, but tolterodine ER was ineffective. In men with a PSA level <1.3 ng/mL, tolterodine ER alone and tolterodine ER plus tamsulosin significantly improved the 24-hour frequency, daytime frequency, frequency-urgency sum, and IPSS storage scores compared with those receiving placebo; tamsulosin alone was ineffective. No significant changes were found in the postvoid residual urine volume or maximal urinary flow rate in any group, and the acute urinary retention rates were low. The results of our study have shown that tolterodine ER was efficacious in men with lower urinary tract symptoms, including overactive bladder, who had lower PSA levels (<1.3 ng/mL).


Effects of ADP on action potential-induced force responses in mechanically skinned rat fast-twitch fibres.
Mechanically skinned muscle fibres from the extensor digitorum longus (EDL) muscle of the rat were electrically stimulated in solutions mimicking the myoplasmic environment in the resting muscle fibre but containing different [ADP] of < 0.1 microm, 40 microm and 1.0 mm, to investigate the effects of myoplasmic ADP on the twitch response. The amplitude of the twitch response markedly and gradually decreased by 47 +/- 6% (n=9) as [ADP] was increased from < 0.1 microm to 40 microm without changing [Ca2+] in the myoplamsic solution (50 nm). The times for the twitch to rise from 10 to 90% (Trise,10-90) and to decrease from 90 to 10% (Tfall,90-10) initially increased by 8 and 21% and then decreased by 16 and 30% (compared to controls), respectively, at steady state. When [ADP] was raised from < 0.1 microm to 1.0 mm and fibres were electrically stimulated, the first response was biphasic and very prolonged (by at least a factor of 10) but of an amplitude similar to that in the control solution. The following twitch response and the steady state twitch responses were much reduced in size by about a factor of 6 and more prolonged by about 40% compared to control responses. All these ADP effects were fully reversible and appear to be predominantly due to several ADP-dependent alterations in SR Ca2+ handling properties (ADP-dependent decrease in SR Ca2+ capacity together with an increase in Ca2+ binding to the SR pump sites facing the myoplasm). The ADP-dependent effects on the contractile apparatus and Ca2+ regulatory system were relatively minor. Taken together, the results demonstrate that ADP accumulation is likely to play a crucial role in metabolic fatigue of skeletal muscle and can explain the marked reduction in the amplitude and the slower time course of the twitch response during fatigue as well as the elevation of myoplasmic [Ca2+] in fatigued fibres at rest.


Spatial measurement of mobility barriers: improving the environment of community-dwelling older adults in Taiwan.
Mobility barriers can impede physical activity, increase the fear of falling, and pose a threat to the ability of older adults to live independently. This study investigated outdoor mobility barriers within a nonretirement public housing community located in Tainan, Taiwan. Site observations and interviews with older adult residents determined that parked motor scooters, potted plants, the rubber tiles of play areas, and a set of steps were the most important barriers. In addition, the space syntax parameters of control value and mean depth were effectively able to quantitatively measure improvements in walkability resulting from the hypothesized removal of these four barriers. These measures of improved walkability can be included in a cost-benefit analysis of spatial improvement factors to help policymakers address the mobility and accessibility needs of older adults.


Deep learning for Alzheimer's disease: Mapping large-scale histological tau protein for neuroimaging biomarker validation.
Abnormal tau inclusions are hallmarks of Alzheimer's disease and predictors of clinical decline. Several tau PET tracers are available for neurodegenerative disease research, opening avenues for molecular diagnosis in vivo. However, few have been approved for clinical use. Understanding the neurobiological basis of PET signal validation remains problematic because it requires a large-scale, voxel-to-voxel correlation between PET and (immuno) histological signals. Large dimensionality of whole human brains, tissue deformation impacting co-registration, and computing requirements to process terabytes of information preclude proper validation. We developed a computational pipeline to identify and segment particles of interest in billion-pixel digital pathology images to generate quantitative, 3D density maps. The proposed convolutional neural network for immunohistochemistry samples, IHCNet, is at the pipeline's core. We have successfully processed and immunostained over 500 slides from two whole human brains with three phospho-tau antibodies (AT100, AT8, and MC1), spanning several terabytes of images. Our artificial neural network estimated tau inclusion from brain images, which performs with ROC AUC of 0.87, 0.85, and 0.91 for AT100, AT8, and MC1, respectively. Introspection studies further assessed the ability of our trained model to learn tau-related features. We present an end-to-end pipeline to create terabytes-large 3D tau inclusion density maps co-registered to MRI as a means to facilitate validation of PET tracers.


The Forensic Lens: Bringing Elder Neglect Into Focus in the Emergency Department.
We present 2 case studies of older patients who were brought to the emergency department (ED) in severely debilitated states. Both presented with severe malnutrition, contractures, and decubitus ulcers, and were nonverbal, with histories of dementia and end-stage disease. Their primary caregivers, adult children, were uncooperative with Adult Protective Services and disregarded treatment recommendations. Although both elders had signs suspicious for neglect, a comprehensive review revealed many layers of complexity. We use these cases to illustrate an approach to the assessment of possible elder neglect in ED settings and how to intervene to ensure patient safety. We begin with a discussion of the differences between willful, unintentional, and unsubstantiated neglect by a caregiver and then describe when to suspect neglect by evaluating the elder, interviewing the caregiver and first responders, assessing the caregiver's ability to meet the elder's needs, and, if possible, obtaining medical history and information about the home care environment. These cases illustrate the importance of careful documentation in cases of suspected neglect to assist investigative agencies, reduce the risk of further harm, and improve patient outcomes.


Pharmacologically induced erect penile length and stretched penile length are both good predictors of post-inflatable prosthesis penile length.
Inflatable penile prosthesis (IPP) remains the gold standard for the surgical treatment of refractory erectile dysfunction; however, current literature to aid surgeons on how best to counsel patients on their postoperative inflated penile length is lacking. The aim of this study was to identify preoperative parameters that could better predict postoperative penile length following insertion of an IPP. Twenty men were enrolled in a prospective study examining penile lengths before and after IPP surgery. Patients with Peyronie's disease were excluded from this analysis. Baseline preoperative characteristics, including body mass index, history of hypertension, diabetes, Sexual Health Inventory for Men scores and/or prior radical prostatectomy were recorded. All patients underwent implantation with a three-piece inflatable Coloplast penile prosthesis. We compared stretched penile length to pharmacologically induced erect lengths. Postoperatively, we measured inflated penile lengths at 6 weeks and assessed patients' perception of penile size at 12 weeks. The median (±interquartile range) stretched penile length and pharmacologically induced erect penile length was 15 (±3) and 14.25 (±2) cm, respectively (P=0.5). Median post-prosthesis penile length (13.5±2.13 cm) was smaller than preoperative pharmacologically induced length (P=0.02) and preoperative stretched penile length (P=0.01). The majority of patients (70%) had a decrease in penile length (median loss 0.5±1.5 cm); however, this loss was perceptible by 43% of men. Stretched penile length and pharmacologically induced erect penile length were equally good predictors of postoperative inflated length (Spearman's correlation 0.8 and 0.9, respectively). Pharmacologically induced erect penile length and stretched penile lengths are equal predictors of post-prosthesis penile length. The majority of men will experience some decrease in penile length following prosthesis implantation; however <50% report a subjective loss of penile length.


Pediatric care for preterm infants after NICU discharge: high number of office visits and prescription medications.
To determine the frequency and risk factors for clinic and pharmacy use in preterm infants during the first year after neonatal intensive care unit (NICU) discharge. We analyzed clinic visits and prescriptions in a cohort of 23 to 32 weeks infants. We constructed multivariable regression models to determine risk factors for high use. The 892 preterm infants experienced 18 346 pediatric visits (mean 20 visits per infant per year) and filled 2100 prescriptions (mean 5.5 prescriptions per year among infants taking medications). Most visits were non-well child care visits to pediatric primary care providers. Prematurity and bronchopulmonary dysplasia (BPD) are important risk factors: infants at 23 to 26 weeks gestation or infants with BPD had an average 29 visits per year and 9 prescriptions per year among infants taking medication. However, half of the highest using infants were relatively healthy infants at 27 to 32 weeks gestation who escaped BPD, NEC or grade 3 to 4 intraventricular hemorrhage. Premature infants had frequent pediatric visits and prescription medications. Extreme prematurity and neonatal morbidities are important risk factors; however, half of the highest using infants are moderately preterm without neonatal morbidities.


Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients.
Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1, and reduced excitability in NR neurons. In addition, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.


MicroRNA function is globally suppressed in mouse oocytes and early embryos.
Dicer, which is required for the processing of both microRNAs (miRNAs) and small interfering RNAs (siRNAs), is essential for oocyte maturation [1, 2]. Oocytes express both miRNAs and endogenous siRNAs (endo-siRNAs) [3, 4]. To determine whether the abnormalities in Dicer knockout oocytes during meiotic maturation are secondary to the loss of endo-siRNAs and/or miRNAs, we deleted Dgcr8, which encodes an RNA-binding protein specifically required for miRNA processing. In striking contrast to Dicer, Dgcr8-deficient oocytes matured normally and, when fertilized with wild-type sperm, produced healthy-appearing offspring, even though miRNA levels were reduced to similar levels as Dicer-deficient oocytes. Furthermore, the deletion of both maternal and zygotic Dgcr8 alleles did not impair preimplantation development, including the determination of the inner cell mass and trophectoderm. Most surprisingly, the mRNA profiles of wild-type and Dgcr8 null oocytes were essentially identical, whereas Dicer null oocytes showed hundreds of misregulated transcripts. These findings show that miRNA function is globally suppressed during oocyte maturation and preimplantation development and that endo-siRNAs, rather than miRNAs, underlie the Dicer knockout phenotype in oocytes.


[Demands on the legal pension security system based on the demographic change].
This paper deals with the German public pension system which is affected by changing demographics. It examines whether the problems can be solved more efficiently by either a fundamental change towards a tax-financed basic allowance augmented by a private capital accumulation sheme, or by adjustments within the present system of wage-determined contributions. The analysis shows that basic allowance and capital accumulation systems are inadequate, essentially for macroeconomic reasons and adverse effects on redistribution, to the demographically induced problems of the public pension system.


Quantitative evaluation of papilledema from stereoscopic color fundus photographs.
To derive a computerized measurement of optic disc volume from digital stereoscopic fundus photographs for the purpose of diagnosing and managing papilledema. Twenty-nine pairs of stereoscopic fundus photographs and optic nerve head (ONH) centered spectral domain optical coherence tomography (SD-OCT) scans were obtained at the same visit in 15 patients with papilledema. Some patients were imaged at multiple visits in order to assess their changes. Three-dimensional shape of the ONH was estimated from stereo fundus photographs using an automated multi-scale stereo correspondence algorithm. We assessed the correlation of the stereo volume measurements with the SD-OCT volume measurements quantitatively, in terms of volume of retinal surface elevation above a reference plane and also to expert grading of papilledema from digital fundus photographs using the Frisén grading scale. The volumetric measurements of retinal surface elevation estimated from stereo fundus photographs and OCT scans were positively correlated (correlation coefficient r(2) = 0.60; P < 0.001) and were positively correlated with Frisén grade (Spearman correlation coefficient r = 0.59; P < 0.001). Retinal surface elevation among papilledema patients obtained from stereo fundus photographs compares favorably with that from OCT scans and with expert grading of papilledema severity. Stereoscopic color imaging of the ONH combined with a method of automated shape reconstruction is a low-cost alternative to SD-OCT scans that has potential for a more cost-effective diagnosis and management of papilledema in a telemedical setting. An automated three-dimensional image analysis method was validated that quantifies the retinal surface topography with an imaging modality that has lacked prior objective assessment.


Atazanavir metabolism according to CYP3A5 status: an in vitro-in vivo assessment.
The current study was a follow-up to an in vivo study in which atazanavir oral clearance was shown to be dependent on genetically determined CYP3A5 expression status, but only in non-African Americans. The aim of this study was to identify atazanavir metabolites generated by CYP3A5 and to evaluate this metabolite pattern in the African-American versus non-African-American CYP3A5 expressors from the previous study. First, the in vitro metabolism of atazanavir was evaluated using human liver microsomes (HLM) and CYP3A4 and CYP3A5 isoforms. Second, the metabolite pattern generated by CYP3A5 was evaluated in human plasma samples from the previous study. Atazanavir metabolites were analyzed using liquid chromatography-tandem mass spectrometry methods. Metabolite areas under the time-concentration curves (AUCs) were normalized to atazanavir AUC to generate an AUC ratio. Sixteen metabolites were observed in human liver microsomal incubations representing five "phase I" biotransformation pathways. Mono-oxidation products (M1 and M2) were formed by CYP3A5 at a faster rate than CYP3A4 by 32- and 2.6-fold, respectively. This finding was replicated in HLM from a genetically determined CYP3A5 expressor versus nonexpressor. In the in vivo samples, the M1 and M2 AUC ratios were approximately 2-fold higher in CYP3A5 expressors versus nonexpressors (P < 0.05), and the difference was similar in African Americans and non-African Americans. Thus, CYP3A5 produced a unique metabolite "signature" for atazanavir in vitro and in vivo, independent of race. Therefore, other pharmacological factors are likely to explain the apparent lack of effect of genetically determined CYP3A5 expressor status on atazanavir oral clearance in African Americans from the previous study.


Deutsche Übersetzung und Validierung des VMIQ-2 zur Erfassung der Lebhaftigkeit von Handlungsvorstellungen.
The aim of the study was to validate a German version of the Vividness of Movement Imagery Questionnaire 2 (VMIQ-2; Roberts, Callow, Hardy, Markland, & Bringer, 2008), which measures external visual, internal visual, and kinesthetic vividness of movement imagery. The psychometric characteristics of the German version did not differ significantly from the English version. Using confirmatory factor analyses, the three-dimensional structure of the VMIQ-2 was replicated with reasonable fit and good internal consistency. The test-retest reliability was moderate. Thus, the German version of the VMIQ-2 is a valid instrument for measuring the vividness of movement imagery.


Pharmacy Preceptor Judgments of Student Performance and Behavior During Experiential Training.
Objective. To report the findings of how Canadian preceptors perceive and subsequently evaluate diverse levels of trainees during pharmacy clerkships. Methods. Using modified Delphi technique, 17 Doctor of Pharmacy (PharmD) preceptors from across Canada categorized 16 student narrative descriptions pertaining to their perception of described student performance: exceeds, meets, or falls below their expectations. Results. Twelve (75%) student narratives profiles were categorized unanimously in the final round, six of which were below expectations. Out of 117 ratings of below expectations by responding preceptors, the majority (115, 98%) of post-baccalaureate PharmD students described would fail. Conversely, if the same narrative instead profiled a resident or an entry-to-practice PharmD student, rotation failure decreased to 95 (81%) and 89 (76%), respectively. Conclusion. Pharmacy preceptors do not uniformly judge the same described student performance and inconsistently apply failing rotation grades when they do agree that performance falls below expectations.


A study on the minimum number of loci required for genetic evaluation using a finite locus model.
For a finite locus model, Markov chain Monte Carlo (MCMC) methods can be used to estimate the conditional mean of genotypic values given phenotypes, which is also known as the best predictor (BP). When computationally feasible, this type of genetic prediction provides an elegant solution to the problem of genetic evaluation under non-additive inheritance, especially for crossbred data. Successful application of MCMC methods for genetic evaluation using finite locus models depends, among other factors, on the number of loci assumed in the model. The effect of the assumed number of loci on evaluations obtained by BP was investigated using data simulated with about 100 loci. For several small pedigrees, genetic evaluations obtained by best linear prediction (BLP) were compared to genetic evaluations obtained by BP. For BLP evaluation, used here as the standard of comparison, only the first and second moments of the joint distribution of the genotypic and phenotypic values must be known. These moments were calculated from the gene frequencies and genotypic effects used in the simulation model. BP evaluation requires the complete distribution to be known. For each model used for BP evaluation, the gene frequencies and genotypic effects, which completely specify the required distribution, were derived such that the genotypic mean, the additive variance, and the dominance variance were the same as in the simulation model. For lowly heritable traits, evaluations obtained by BP under models with up to three loci closely matched the evaluations obtained by BLP for both purebred and crossbred data. For highly heritable traits, models with up to six loci were needed to match the evaluations obtained by BLP.


The influence of supplementation with artichoke (Cynara scolymus L.) extract on selected redox parameters in rowers.
High-intensity physical exercise decreases intracellular antioxidant potential. An enhanced antioxidant defense system is desirable in people subjected to exhaustive exercise. The aim of this study was to investigate the influence of supplementation with artichoke-leaf extract on parameters describing balance between oxidants and antioxidants in competitive rowers. This double-blinded study was carried out in 22 members of the Polish rowing team who were randomly assigned to a supplemented group (n = 12), receiving 1 gelatin capsule containing 400 mg of artichoke-leaf extract 3 times a day for 5 wk, or a placebo group (n = 10). At the beginning and end of the study participants performed a 2,000-m maximal test on a rowing ergometer. Before each exercise test, 1 min after the test completion, and after a 24-hr restitution period blood samples were taken from antecubital vein. The following redox parameters were assessed in red blood cells: superoxide dismutase activity, glutathione peroxidase activity, glutathione reductase activity, reduced glutathione levels, and thiobarbituric-acid-reactive-substances concentrations. Creatine kinase activity and total antioxidant capacity (TAC) were measured in plasma samples, lactate levels were determined in capillary blood samples, and serum lipid profiles were assessed. During restitution, plasma TAC was significantly higher (p < .05) in the supplemented group than in the placebo group. Serum total cholesterol levels at the end of the study were significantly (p < .05) lower in the supplemented group than in the placebo group. In conclusion, consuming artichoke-leaf extract, a natural vegetable preparation of high antioxidant potential, resulted in higher plasma TAC than placebo but did not limit oxidative damage to erythrocytes in competitive rowers subjected to strenuous training.


Association of vena cava filters and catheter-directed thrombolysis for deep vein thrombosis with hospital readmissions.
Acute deep vein thrombosis (DVT) affects >350,000 patients each year in the United States. Contemporary rehospitalization rates and predictors of acute DVT have not been well-characterized. We aimed to evaluate the all-cause 30-day readmission rate and its association with catheter-directed thrombolysis and vena cava filters in patients with proximal and caval DVT. Patients with an index hospitalization for acute proximal lower extremity DVT were evaluated for unplanned readmission rates at 30 days using the Nationwide Readmission Database from 2016 to 2017. We used Cox proportional hazard model to determine the predictors of 30-day readmissions and their association with inferior vena cava (IVC) filter and CDT use. We identified 58,306 adult patients with an index hospitalization for acute proximal DVT. The unplanned 30-day rehospitalization rate was 14.7% (95% confidence interval [CI], 14.5-15.0%). There were 4995 patients (10.0%) who underwent CDT and 6085 (12.2%) who underwent IVC filter placement. In multivariable analysis, only CDT was associated with a lower hazard for rehospitalization (hazard ratio [HR], 0.77; 95% CI, 0.71-0.84; P < .001), whereas IVC filter placement (HR, 1.26; 95% CI, 1.19-1.34; P < .001), Charlson Comorbidity Index of >3 (HR, 1.47; 95% CI, 1.38-1.56; P < .001), malignancy (HR, 1.45; 95% CI, 1.34-1.57; P < .001), and length of stay >5 days (HR, 1.39; 95% CI, 1.33-1.46; P < .001), and acute kidney injury (HR, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with higher readmission rates. The 30-day unplanned rehospitalization rate continues to be high in patients with acute proximal DVT. CDT was associated with lower rehospitalization rates, whereas IVC filter placement was associated with increased rehospitalization rates.


Markers of experimental acute inflammation in the Wistar Han rat with particular reference to haptoglobin and C-reactive protein.
C-reactive protein (CRP), haptoglobin (Hp) and fibrinogen (Fbgn) are acute phase reactants (APRs), the blood levels of which increase during acute inflammation. However, although the levels of these APRs are used to monitor inflammation in man, their usefulness and sensitivity as markers of inflammation in rodents are less clear. We therefore wished to evaluate, in a comparative fashion, a prototype immunoassay for serum CRP, a commercial assay for serum Hp, and an automated assay for Fbgn, using a model of acute inflammation in the rat. Additionally, pro-inflammatory cytokines and serum protein fractions were also measured. The model of inflammation used was the intraperitoneal injection of Freund's complete adjuvant (FCA). In a concluding experiment, findings with Hp in the FCA rat model were validated in a toxicologically relevant study involving the induction of acute hepatic inflammation using the model hepatotoxicant carbon tetrachloride (CCl(4)). Female Wistar Han rats were treated with a single injection of FCA in a dose-response study (1.25-10.0 ml/kg, sampling at 36 h) and two time-course studies (over 40 h and 21 days). In a final experiment, rats were dosed with CCl(4) at 0.8 ml/kg and sampled over a 17-day period. In FCA and CCl(4) experiments, serum/plasma was prepared and tissues taken at autopsy for histological assessment (CCl(4) study only). In the dose-response study, serum CRP, Hp and plasma Fbgn were increased at all FCA dose levels at 36 h post-dosing. Serum alpha(2) and beta(1) globulin fractions were also increased, while albumin levels were decreased. In the 40-h time-course study, CRP levels peaked at 25-40 h post-dosing, to approximately 120% of control (as 100%). Hp levels increased to a maximum at 25 and 40 h post-dosing with values greater than 400% of control, and alpha(2) and beta(1) globulin fractions peaked at 30 and 40 h post-dosing to 221 and 187% of control, respectively. Increased serum interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) levels peaked at 20 h (11-fold) and 25 h (19-fold), respectively. In a 21-day time-course study, no increased CRP levels were measured despite elevated levels of Hp, which peaked at 36 h (approximately 7-fold above control), and remained elevated up to 21 days. IL-6 and IL-1beta levels peaked at 12 h (19-fold) and 24 h (28-fold), respectively. Liver histopathology of animals treated with CCl(4) showed centrilobular hepatocellular degeneration and necrosis (most significant at 36 h) with an inflammatory response (most significant at 48 h). Resolution of the lesion was complete by 4 days post-dosing. Serum alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase levels peaked at 36 h post-dosing. Hp levels increased maximally at 48 h (426% of control). We conclude that serum CRP is a poor marker of acute inflammation in the rat in comparison with serum Hp and plasma Fbgn. Between Hp and Fbgn, serum Hp is shown to be the most sensitive and useful marker of acute inflammation.


Understanding Non-Mendelian Genetic Risk.
This opinion paper highlights strategies for a better understanding of non-Mendelian genetic risk that was revealed by genome-wide association studies (GWAS) of complex diseases. The genetic risk resides predominantly in non-coding regulatory DNA, such as in enhancers. The identification of mechanisms, the causal variants (mainly SNPs), and their target genes are, however, not always apparent but are likely involved in a network of risk determinants; the identification presents a bottle-neck in the full understanding of the genetics of complex phenotypes. Here, we propose strategies to identify functional SNPs and link risk enhancers with their target genes. The strategies are 1) identifying fine-mapped SNPs that break/form response elements within chromatin bio-features in relevant cell types 2) considering the nearest gene on linear DNA, 3) analyzing eQTLs, 4) mapping differential DNA methylation regions and relating them to gene expression, 5) employing genomic editing with CRISPR/cas9 and 6) identifying topological associated chromatin domains using chromatin conformation capture.


The Research Progress in Transforming Growth Factor-β2.
Transforming growth factor-beta 2 (TGF-β2), an important member of the TGF-β family, is a secreted protein that is involved in many biological processes, such as cell growth, proliferation, migration, and differentiation. TGF-β2 had been thought to be functionally identical to TGF-β1; however, an increasing number of recent studies uncovered the distinctive features of TGF-β2 in terms of its expression, activation, and biological functions. Mice deficient in TGF-β2 showed remarkable developmental abnormalities in multiple organs, especially the cardiovascular system. Dysregulation of TGF-β2 signalling was associated with tumorigenesis, eye diseases, cardiovascular diseases, immune disorders, as well as motor system diseases. Here, we provide a comprehensive review of the research progress in TGF-β2 to support further research on TGF-β2.


Inflammatory modulation of fluoxetine use in patients with depression: A systematic review and meta-analysis.
There is growing evidence that there is a relationship between major depressive disorder (MDD), also simply known as "depression", and inflammatory processes. Selective serotonin inhibitors, such as fluoxetine, are used as a first-line treatment for depression, and it is hypothesized that its use can reduce levels of proinflammatory cytokines. The aim of this systematic review and meta-analysis is to enable a better understanding of how treatment with the antidepressant fluoxetine modulates inflammation, and the roles of the main cytokines in this process. Risk of bias (RoB) in the included studies was assessed using the Cochrane Risk of Bias Assessment tool for Non-randomized studies (RoBANS). In the meta-analysis, standardized mean difference (SMD) was used as a summary statistic and grouped statistics using the generic inverse variation method in RevMan 5 with random effects model. Heterogeneous changes in cytokine levels were also evaluated from the SMD forest plot of individual studies. After analysis, we observed that fluoxetine was able to decrease TNF-α levels (SMD ± 0.90, 95% CI = 0.16, 1.165, Z ± 2.40, p = 0.02), but not change IL-6 levels (SMD ± 0.37, 95% CI = 0.21, 0.95, Z ± 1.25, p = 0.21).Fluoxetine acts by modulating neuroimmunology, and not only by acting only on the independent restoration of neurotransmission and neuroinflammation pathways.


Reproducing chaos by variable structure recurrent neural networks.
In this paper, we present a new approach for chaos reproduction using variable structure recurrent neural networks (VSRNN). A neural network identifier is designed, with a variable structure that will change according to its output performance as compared to the given orbits of an unknown chaotic systems. A tradeoff between identification errors and computational complexity is discussed.


Abdominal wall closure after intestinal transplantation.
Successful surgical closure of the abdominal wall after either combined or isolated intestinal transplantation may present a challenging dilemma for the plastic and reconstructive surgeon because of the following factors: restricted volume of the recipient abdominal cavity; donor-recipient size discrepancies as expressed by the donor to recipient weight ratio; and significant intraoperative edema. The purpose of this investigation is to present clinical experience with 51 consecutive patients who underwent a total of 57 sequential intestinal transplantations at the University of Miami-Jackson Memorial Hospital. A retrospective chart review of 36 pediatric (63 percent) and 21 adult (37 percent) transplantations was performed. Age of the pediatric population ranged from 1 month to 13 years (mean, 2.4 years) and of the adult population from 22 to 55 years (mean, 33.5 years). Several diagnostic classifications necessitated organ transplantation. Because of insufficient donor graft size for the recipient abdominal cavity in 19 transplantations (33 percent), several technical modifications were used to achieve anatomic and functional abdominal wall closure in all patients. In summary, the plastic and reconstructive surgeon should have a significant role in the comprehensive planning and management of abdominal wall closure in this challenging group of patients.


Antimicrobial susceptibility testing of Francisella tularensis with a modified Mueller-Hinton broth.
A modified Mueller-Hinton broth was developed to perform antimicrobial susceptibility tests on Francisella tularensis. Adequate growth of the organism was obtained within 24 h of inoculation, and MICs could be read at that time. We tested 15 selected strains of F. tularensis and five reference quality control strains in this medium with 36 antimicrobial agents. The MICs of the aminoglycosides and tetracycline increased 1 to 3 dilutions in this medium compared with those in the usual medium, but the other antimicrobial agents were not consistently affected by the medium. Even though the medium caused an increase in MICs, the aminoglycosides and tetracyclines remained very active in vitro against F. tularensis. Other antimicrobial agents effective in vitro were chloramphenicol, erythromycin, ceftazidime, moxalactam, cefotaxime, ceftriaxone, and Sch 29482 (a cephalosporin).


Benchmarking Catalysts for Formic Acid/Formate Electrooxidation.
Energy production and consumption without the use of fossil fuels are amongst the biggest challenges currently facing humankind and the scientific community. Huge efforts have been invested in creating technologies that enable closed carbon or carbon neutral fuel cycles, limiting CO2 emissions into the atmosphere. Formic acid/formate (FA) has attracted intense interest as a liquid fuel over the last half century, giving rise to a plethora of studies on catalysts for its efficient electrocatalytic oxidation for usage in fuel cells. However, new catalysts and catalytic systems are often difficult to compare because of the variability in conditions and catalyst parameters examined. In this review, we discuss the extensive literature on FA electrooxidation using platinum, palladium and non-platinum group metal-based catalysts, the conditions typically employed in formate electrooxidation and the main electrochemical parameters for the comparison of anodic electrocatalysts to be applied in a FA fuel cell. We focused on the electrocatalytic performance in terms of onset potential and peak current density obtained during cyclic voltammetry measurements and on catalyst stability. Moreover, we handpicked a list of the most relevant examples that can be used for benchmarking and referencing future developments in the field.


A potential means of improving the evaluation of deformity corrections with Taylor spatial frames over time by using volumetric imaging: preliminary results.
In this study we explore the possibility of accurately and cost-effectively monitoring tibial deformation induced by Taylor Spatial Frames (TSFs), using time-separated computed tomography (CT) scans and a volume fusion technique to determine tibial rotation and translation. Serial CT examinations (designated CT-A and CT-B, separated by a time interval of several months) of two patients were investigated using a previously described and validated volume fusion technique, in which user-defined landmarks drive the 3D registration of the two CT volumes. Both patients had undergone dual osteotomies to correct for tibial length and rotational deformity. For each registration, 10 or more landmarks were selected, and the quality of the fused volume was assessed both quantitatively and via 2D and 3D visualization tools. First, the proximal frame segment and tibia in CT-A and CT-B were brought into alignment (registered) by selecting landmarks on the frame and/or tibia. In the resulting "fused" volume, the proximal frame segment and tibia from CT-A and CT-B were aligned, while the distal frame segment and tibia from CT-A and CT-B were likely not aligned as a result of tibial deformation or frame adjustment having occurred between the CT scans. Using the proximal fused volume, the distal frame segment and tibia were then registered by selecting landmarks on the frame and/or tibia. The difference between the centroids of the final distal landmarks was used to evaluate the lengthening of the tibia, and the Euler angles from the registration were used to evaluate the rotation. Both the frame and bone could be effectively registered (based on visual interpretation). Movement between the proximal frame and proximal bone could be visualized in both cases. The spatial effect on the tibia could be both visually assessed and measured: 34 mm, 10 degrees in one case; 5 mm, 1 degrees in the other. This retrospective analysis of spatial correction of the tibia using Taylor Spatial Frames shows that CT offers an interesting potential means of quantitatively monitoring the patient's treatment. Compared with traditional techniques, modern CT scans in conjunction with image processing provide a high-resolution, spatially correct, and three-dimensional measurement system which can be used to quickly and easily assess the patient's treatment at low cost to the patient and hospital.


Critical effect of pore characteristics on capillary infiltration in mesoporous films.
Capillary phenomena governing the mass-transport (capillary filling, condensation/evaporation) has been experimentally investigated in around 20 different silica thin films exhibiting various porosities with pores dimension ranging from 2 to 200 nm. Films have been prepared by sol-gel chemistry combined with soft-templating approaches and controlled dip coating process. Environmental ellipsometric porosimetry combined with electronic microscopy were used to assess the porosity characteristics. Investigation of lateral capillary filling was performed by following the natural infiltration of water and ionic liquids at the edge of a sessile drop in open air or underneath a PDMS cover. The Washburn model was applied to the displacement of the liquid front within the films to deduce the kinetic constants. The role of the different capillary phenomena were discussed with respect to the porosity characteristics (porosity vol%, pore dimensions and constrictions). We show that correlation between capillary filling rate and pore dimensions is not straightforward. Generally, with a minimum of constrictions, faster filling is observed for larger pores. In the case of mesopores (<50 nm in diameter), the presence of bottle necks considerably slows down the infiltration rate. At such a small dimension, evaporation/capillary condensation dynamics, taking place at the meniscus inside the porosity, has to be considered to explain the transport mode. This fundamental study is of interest for applications involving liquids at the interface of mesoporous networks such as nanofluidics, purification, separation, water harvesting or heat transfer.


Significantly Enhanced Energy-Saving H2 Production Coupled with Urea Oxidation by Low- and Non-Pt Anchored on NiS-Based Conductive Nanofibers.
Rational designing electrocatalysts is of great significance for realizing high-efficiency H2 production in the water splitting process. Generally, reducing the usage of precious metals and developing low-potential nucleophiles oxidation reaction to replace anodic oxygen evolution reaction (OER) are efficient strategies to promote H2 generation. Here, NiS-coated nickel-carbon nanofibers (NiS@Ni-CNFs) are prepared for low-content Pt deposition (Pt-NiS@Ni-CNFs) to attain the alkaline HER catalyst. Due to the reconfiguration of NiS phase and synergistic effect between Pt and nickel sulfides, the Pt-NiS@Ni-CNFs catalyst shows a high mass activity of 2.74-fold of benchmark Pt/C sample. In addition, the NiS@Ni-CNFs catalyst performs a superior urea oxidation reaction (UOR) activity with the potential of 1.366 V versus reversible hydrogen electrode (RHE) at 10 mA cm-2 , which demonstrates the great potential in the replacement of OER. Thus, a urea-assisted water splitting electrolyzer of Pt-NiS@Ni-CNFs (cathode)||NiS@Ni-CNFs (anode) is constructed to exhibit small voltages of 1.44 and 1.65 V to reach 10 and 100 mA cm-2 , which is much lower than its overall water splitting process, and presents a 6.5-fold hydrogen production rate enhancement. This work offers great opportunity to design new catalysts toward urea-assisted water splitting with significantly promoted hydrogen productivity and reduced energy consumption.


Alone Yet Not Alone: Frankia Lives Under the Same Roof With Other Bacteria in Actinorhizal Nodules.
Actinorhizal plants host mutualistic symbionts of the nitrogen-fixing actinobacterial genus Frankia within nodule structures formed on their roots. Several plant-growth-promoting bacteria have also been isolated from actinorhizal root nodules, but little is known about them. We were interested investigating the in planta microbial community composition of actinorhizal root nodules using culture-independent techniques. To address this knowledge gap, 16S rRNA gene amplicon and shotgun metagenomic sequencing was performed on DNA from the nodules of Casuarina glauca. DNA was extracted from C. glauca nodules collected in three different sampling sites in Tunisia, along a gradient of aridity ranging from humid to arid. Sequencing libraries were prepared using Illumina NextEra technology and the Illumina HiSeq 2500 platform. Genome bins extracted from the metagenome were taxonomically and functionally profiled. Community structure based off preliminary 16S rRNA gene amplicon data was analyzed via the QIIME pipeline. Reconstructed genomes were comprised of members of Frankia, Micromonospora, Bacillus, Paenibacillus, Phyllobacterium, and Afipia. Frankia dominated the nodule community at the humid sampling site, while the absolute and relative prevalence of Frankia decreased at the semi-arid and arid sampling locations. Actinorhizal plants harbor similar non-Frankia plant-growth-promoting-bacteria as legumes and other plants. The data suggests that the prevalence of Frankia in the nodule community is influenced by environmental factors, with being less abundant under more arid environments.


Mania in the Swedish Twin Registry: criterion validity and prevalence.
In population surveys, the assessment of mania is commonly done by trained lay interviewers using structured diagnostic instruments: the validity of this approach has been questioned. We examined the criterion validity and prevalence of lifetime mania in a survey of Swedish twins conducted with interview methodology usually applied in psychiatric epidemiology. 41 838 individuals in the Swedish Twin Registry were evaluated via a telephone interview that included the eight DSM-IV mania items, and these data were merged with inpatient hospitalization discharge diagnoses from two comprehensive national registries (the criterion). An algorithm with eight cut-points was used to diagnose lifetime mania, and compared by a receiver operator characteristic curve to the criterion. The algorithm requiring at least four positive items resembling a DSM-IV diagnosis. History of hospitalization for a psychiatric condition that included a manic episode was present for 0.7% of all living twins, and predicted non-response to the survey (OR = 0.5; 95% CI = 0.4-0.6). The incidence rate for first hospitalization was 2.1/10 000 year(-1). For > or =1 symptom (first cut-point), the prevalence, sensitivity and specificity were 3.6%, 39.0% and 96.6%; for > or = 4 symptoms (DSM-IV-like cut-point) 2.6%, 36.5% and 97.6%; and for eight symptoms 0.3%, 18.0% and 99.8%. Positive predictive values were, respectively, 5.5%, 7.0% and 29.8%. The performance of the telephone screening for mania by lay interviewers in terms of positive predictive power was not satisfactory; despite a high specificity, the false positive rate was high. The low population prevalence of mania, non-response bias, criterion choice and inherent limitations of the interviewing method are among the explanations. Assessment of a lifetime manic episode based on lay interviewer screening may yield misleading data.


Comparison of several non-linear-regression methods for fitting the Michaelis-Menten equation.
The known jackknife methods (i.e. standard jackknife, weighted jackknife, linear jackknife and weighted linear jackknife) for the determination of the parameters (as well as of their confidence regions) were tested and compared with the simple Marquardt's technique (comprising the calculation of confidence intervals from the variance-co-variance matrix). The simulated data corresponding to the Michaelis-Menten equation with defined structure and magnitude of error of the dependent variable were used for fitting. There were no essential differences between the results of both point and interval parameter estimations by the tested methods. Marquardt's procedure yielded slightly better results than the jackknives for five scattered data points (the use of this method is advisable for routine analyses). The classical jackknife was slightly superior to the other methods for 20 data points (this method can be recommended for very precise calculations if great numbers of data are available). The weighting does not seem to be necessary in this type of equation because the parameter estimates obtained with all methods with the use of constant weights were comparable with those calculated with the weights corresponding exactly to the real error structure whereas the relative weighting led to rather worse results.


Intermittent Theta Burst Stimulation Over Ventral Premotor Cortex or Inferior Parietal Lobule Does Not Enhance the Rubber Hand Illusion.
An enhanced sense of prosthesis ownership may be the key for higher amputees' quality of life. In this study in 28 healthy subjects, neuronavigated intermittent Theta Burst Stimulation (iTBS) delivered over the right ventral premotor cortex or inferior parietal lobule has been tested, compared to sham stimulation, to enhance embodiment in the rubber hand illusion paradigm. Neuromodulation of both areas did not result in an enhancement of embodiment, as assessed by the results collected from a self-evaluation questionnaire for the extent of self-attribution of the rubber hand and proprioceptive drift. In all cases, the difference between synchronous and asynchronous stroking confirms the successful induction of the illusion. It may be speculated that the low consistency of iTBS over brain regions other than primary motor cortex may account for the absence of effect, suggesting to test other neuromodulating techniques, acting on cortical networks different from the ones sensitive to iTBS to enhance artificial hand embodiment.


Australian suicide trends 1964-1997: youth and beyond?
To examine Australian suicide rates across all ages, and compare Australian rates with those of other Western nations. Australian Bureau of Statistics data were used to examine Australian suicide trends, 1964-1997, by age and sex. For comparison, suicide rates of 22 other Western nations, 1990-1994, were obtained from the World Health Organization. Australian suicide rates for males 15-24 years and 25-34 years rose from 1964-1997. Comparable rates for females showed no significant change. Suicide rates for several of the older age and sex groups declined over this period. Comparison with suicide rates of other Western nations showed that, while Australian youth suicide rates are relatively high, this is not the case for older age groups. Australian suicide rates are higher than those in the European nations of origin of our major migrant groups, but similar to those of other Western nations also recently colonised by Europeans (Canada, the United States and New Zealand). Priorities for suicide prevention in Australia are correctly concentrated on youth, but the targeted age range should be extended to include men aged 25-34 years. A comprehensive policy should also not neglect the needs of other age groups. Further epidemiological study of national and international data may suggest new approaches to suicide prevention.


High yield expression and purification of isotopically labelled human endothelin-1 for use in NMR studies.
Human endothelin-1 (ET-1) is a potent vasocontractile 21-residue peptide hormone with significant pharmacological importance. An efficient and straightforward expression strategy that enables cost-effective incorporation of stable isotopes is not available thus far. In this report, we describe a cost-effective expression system in Escherichia coli for the production of ET-1 enriched with (15)N and (13)C isotopes. Employing thioredoxin as carrier protein, specific and nearly quantitative cleavage of ET-1 from the fusion was mediated by Factor Xa, and purification to homogeneity (final purity of >95%) was achieved by RP-HPLC. Purified recombinant ET-1 was found to be indistinguishable from the synthetic counterpart as determined by mass spectrometry and NMR spectroscopy. Our expression strategy offers the potential for production of isotopically labeled ET-1 in large (mg) quantities for the purpose of heteronuclear NMR experiments. Moreover, the method devised should be applicable for recombinant expression of small peptides in general.


Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.
The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide.


Modulation in the developmental expression profile of Sp1 subsequent to transplacental exposure of fetal rats to desorbed benzo[a]pyrene following maternal inhalation.
Any alteration of the critical sequence of genes that are required to coordinate the differentiation of cells, the promotion of migration, dendritic arborization, synapse formation, and myelination in the developing nervous system would be expected to have deleterious consequences. The focus of this article is a molecular evaluation of the neurotoxicological effects that result subsequent to the transplacental exposure of fetal rats to desorbed benzo(a)pyrene (BaP) following maternal inhalation. A state-of-the-art, newly designed, fabricated, and tested model aerosol generation system was utilized in these studies. Timed-pregnant Sprague Dawley rats were exposed for 4 h on gestation day 15 of a 21-day gestation period to an acute dose of BaP:carbon black aerosol (100 microg/m(3)). Controls received carbon black only. Nominal and chamber concentrations of the particulate aerosol were determined gravimetrically with a seven-stage cascade impactor. The aerosol exhibited a trimodal distribution with 95% cumulative mass less than 15.85 microm, 90% cumulative mass less than 10 microm, 67. 5% cumulative mass less than 2.5 microm and 66.2% cumulative mass less than 1.0 microm. Time-course bioavailability results indicated that greater than 95% of the parent compound is cleared from blood 240 min postexposure. An Sp1 transcription factor consensus sequence was examined by electrophoretic mobility shift analysis of nuclear extracts from various brain regions of resulting pups on postnatal days 3, 5, 7, 10, and 15. It revealed perturbations in the developmental expression profile of Sp1 abundance as a result of nose-only particulate aerosol exposure to the timed-pregnant dam. The data obtained on the temporal and spatial regulation of gene expression in the brain indicate that (1) Sp1 DNA-binding is developmentally regulated and expressed very highly in actively developing brain regions, and (2) a consequence of the transplacental deposition of desorbed BaP to the fetus is in utero neurotoxicity.


New reference values for forced spirometry in white adults in Brazil.
To describe spirometric reference equations for healthy Brazilian adults who have never smoked and to compare the predicted values with those derived in 1992. Reference equations for spirometry were derived in 270 men and 373 women living in eight cities in Brazil. Ages ranged from 20 to 85 years in women and from 26 to 86 years in men. Spirometry examinations followed the recommendations of the Brazilian Thoracic Society. Lower limits were derived by the analysis of the fifth percentiles of the residuals. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC and FEV1/forced expiratory volume in six seconds (FEV6) were best fitted by linear regression. Flows were best fitted using log equations. For both genders, greater height resulted in lower values for FEV1/FVC, FEV1/FEV6 and flow/FVC ratios. The reference values for FEV1 and FVC in the present study were higher than those derived for Brazilian adults in 1992. New predicted values for forced spirometry were obtained in a sample of white Brazilians. The values are greater than those obtained in 1992, probably due to technical factors.


Internal Structure of 15 nm 3-Helix Micelle Revealed by Small-Angle Neutron Scattering and Coarse-Grained MD Simulation.
3-Helix micelles (3HM) formed by self-assembly of peptide-polymer conjugate amphiphiles have shown promise as a nanocarrier platform due to their long-circulation, deep tumor penetration, selective accumulation in tumor, and ability to cross the blood-brain barrier (BBB) for glioblastoma therapy. There is a need to understand the structural contribution to the high in vivo stability and performance of 3HM. Using selective deuteration, the contrast variation technique in small-angle neutron scattering, and coarse-grained molecular dynamics simulation, we determined the spatial distribution of each component within 3HM. Our results show a slightly deformed polyethylene glycol (PEG) conformation within the micelle that is radially offset from its conjugation site toward the exterior of the micelle and a highly solvated shell. Surprisingly, ∼85 v/v % of 3HM is water, unusually higher than any micellar nanocarrier based on our knowledge. The result will provide important structural insights for future studies to uncover the molecular origin of 3HM's in vivo performance, and development of the nanocarriers.


A Metabolic Obesity Profile Is Associated With Decreased Gray Matter Volume in Cognitively Healthy Older Adults.
Obesity is a risk factor for cognitive decline and gray matter volume loss in aging. Studies have shown that different metabolic factors, e.g., dysregulated glucose metabolism and systemic inflammation, might mediate this association. Yet, even though these risk factors tend to co-occur, they have mostly been investigated separately, making it difficult to establish their joint contribution to gray matter volume structure in aging. Here, we therefore aimed to determine a metabolic profile of obesity that takes into account different anthropometric and metabolic measures to explain differences in gray matter volume in aging. We included 748 elderly, cognitively healthy participants (age range: 60 - 79 years, BMI range: 17 - 42 kg/m2) of the LIFE-Adult Study. All participants had complete information on body mass index, waist-to-hip ratio, glycated hemoglobin, total blood cholesterol, high-density lipoprotein, interleukin-6, C-reactive protein, adiponectin and leptin. Voxelwise gray matter volume was extracted from T1-weighted images acquired on a 3T Siemens MRI scanner. We used partial least squares correlation to extract latent variables with maximal covariance between anthropometric, metabolic and gray matter volume and applied permutation/bootstrapping and cross-validation to test significance and reliability of the result. We further explored the association of the latent variables with cognitive performance. Permutation tests and cross-validation indicated that the first pair of latent variables was significant and reliable. The metabolic profile was driven by negative contributions from body mass index, waist-to-hip ratio, glycated hemoglobin, C-reactive protein and leptin and a positive contribution from adiponectin. It positively covaried with gray matter volume in temporal, frontal and occipital lobe as well as subcortical regions and cerebellum. This result shows that a metabolic profile characterized by high body fat, visceral adiposity and systemic inflammation is associated with reduced gray matter volume and potentially reduced executive function in older adults. We observed the highest contributions for body weight and fat mass, which indicates that factors underlying sustained energy imbalance, like sedentary lifestyle or intake of energy-dense food, might be important determinants of gray matter structure in aging.


Unfractionated heparin reduces the elasticity of sputum from patients with cystic fibrosis.
Mucus obstruction of the airway in patients with cystic fibrosis (CF) reduces lung function, invites infection, and limits delivery of inhaled drugs including gene therapy vectors to target cells. Not all patients respond to presently available mucolytics, and new approaches are needed. Our objectives were to investigate the in vitro effects of unfractionated heparin (UFH) on the morphology and rheology of sputum and the effect of UFH on diffusion of 200-nm nanospheres through sputum from adult CF patients. Confocal laser scanning microscopy was used to image fluorescently stained actin and DNA components of CF sputum, and atomic force microscopy was used to image isolated DNA networks. The viscoelasticity of CF sputum was measured using dynamic oscillatory rheometry. Nanosphere diffusion was measured through CF sputum using a Boyden chamber-based assay. Actin-DNA bundles in CF sputum were disaggregated by UFH at concentrations of 0.1-10 mg/ml, and UFH enhanced the endonuclease activity in sputum from patients on dornase alfa therapy. UFH significantly reduced the elasticity and yield stress, but not the viscosity, of CF sputum from patients not receiving dornase alfa therapy. Heparin dose-dependently significantly increased the diffusion of nanospheres through CF sputum from patients not on dornase alfa therapy from 10.5 +/- 2.5% at baseline to 36.9 +/- 4.4% at 10 mg/ml but was more potent, with maximal effect at 0.1 mg/ml, in patients who were on dornase alfa therapy. Thus the mucoactive properties of UFH indicate its potential as a new therapeutic approach in patients with cystic fibrosis.


SLC30A8 nonsynonymous variant is associated with recovery following exercise and skeletal muscle size and strength.
Genome-wide association studies have identified thousands of variants that are associated with numerous phenotypes. One such variant, rs13266634, a nonsynonymous single nucleotide polymorphism in the solute carrier family 30 (zinc transporter) member eight gene, is associated with a 53% increase in the risk of developing type 2 diabetes (T2D). We hypothesized that individuals with the protective allele against T2D would show a positive response to short-term and long-term resistance exercise. Two cohorts of young adults-the Eccentric Muscle Damage (EMD; n = 156) cohort and the Functional Single Nucleotide Polymorphisms Associated with Muscle Size and Strength Study (FAMuSS; n = 874)-were tested for association of the rs13266634 variant with measures of skeletal muscle response to resistance exercise. Our results were sexually dimorphic in both cohorts. Men in the EMD study with two copies of the protective allele showed less post-exercise bout strength loss, less soreness, and lower creatine kinase values. In addition, men in the FAMuSS, homozygous for the protective allele, showed higher pre-exercise strength and larger arm skeletal muscle volume, but did not show a significant difference in skeletal muscle hypertrophy or strength with resistance training.


Prognostic factors and treatment outcomes in patients with non-ampullary small bowel adenocarcinoma: Long-term analysis.
Small bowel adenocarcinoma (SBA) is a relatively rare malignancy in gastrointestinal tumors. In addition, the difficulty of early diagnosis, its poor prognosis compared to large bowel adenocarcinoma, and inadequate treatment experiences due to lack of prospective randomized trials make it necessary to explore the characteristics of the disease for early diagnosis and treatment.Patients diagnosed with primary malignant tumor of small intestine in West China Hospital of Sichuan University between January 2001 and 2013 were reviewed retrospectively. A total of 208 patients with SBA were selected and 160 patients with duodenal periampullary tumor were excluded. Forty-two cases of patients were finally enrolled for statistical analysis as 6 patients were lost of follow-up. The clinical characteristics, the response to treatment and their overall survival (OS) time were reviewed and analyzed.Of the 42 patients, 11 (26.2%) primary tumors were originated from duodenum, 29 (69.0%) from jejunum, and 2 (4.8%) from ileum. All patients (64.3% male; median age, 54.7 years) included in this study underwent primary resection of the tumor to confirm final diagnosis. Three-year survival rate is 21% and 5-year survival rate is 9%. Median OS were 24.2 months (95% CI: 4.0-72.0). The univariate predictors for prognosis of SBA were as follows: age (P = .021), severe intestinal symptoms at first diagnosis (P < .001), T4 of tumor stage (P = .011), tumor size (P = .004), relatively late clinical stage (P < .001), peritoneal metastasis (P < .001), and no chemotherapy (P = .011). The multivariate predictors for poor prognosis were age of more than 60 years old (P = .035), intestinal obstruction or perforation at first diagnosis (P = .026), relatively late clinical stage (P = .000), and no chemotherapy (P = .027).SBA was a relatively rare malignancy that was difficult for early diagnosis and treatment. Intestinal obstruction was the common clinical manifestation at first diagnosis, with a tendency of early peritoneal metastasis. Precaution of the disease in early phase, radical resection of the primary tumor while resectable, followed with in-time chemotherapy might improve prognosis and survival of patients with SBA.


Home glucose monitoring for insulin-dependent diabetics: preliminary results.
Home glucose monitoring is one of several new and aggressive approaches to improving blood glucose homeostasis in the insulin-deficient diabetic. The advent of a successful long-term pancreatic transplant or a reliable miniaturized artificial pancreas may, soon, supercede it as a treatment modality, but for the time it would appear that home glucose monitoring is a viable alternative to the more conventional and less successful methods of control and should at least be considered for use in patients with insulin-deficient diabetes mellitus.


Synthesis of D-mannose capped silicon nanoparticles and their interactions with MCF-7 human breast cancerous cells.
Silicon nanoparticles (SiNPs) hold prominent interest in various aspects of biomedical applications. For this purpose, surface functionalization of the NPs is essential to stabilize them, target them to specific disease area, and allow them to selectively bind to the cells or the bio-molecules present on the surface of the cells. However, no such functionalization has been explored with Si nanoparticles. Carbohydrates play a critical role in cell recognition. Here, we report the first synthesis of silicon nanoparticles functionalized with carbohydrates. In this study, stable and brightly luminescent d-Mannose (Man) capped SiNPs have been synthesized from amine terminated SiNPs and d-mannopyranoside acid. The surface functionalization is confirmed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), and energy dispersive X-ray spectroscopy (EDX) studies. The mean diameter of the crystal core is 5.5 nm, as measured by transmission electron microscopy (TEM), while the hydrodynamic diameter obtained by dynamic light scattering (DLS) is 16 nm. The quantum yield (QY) of photoluminescence emission is found to be 11.5%, and the nanoparticles exhibit an exceptional stability over two weeks. The Man-capped SiNPs may prove to be valuable tools for further investigating glycobiological, biomedical, and material science fields. Experiments are carried out using Concanavalin A (ConA) as a target protein in order to prove the hypothesis. When Man functionalized SiNPs are treated with ConA, cross-linked aggregates are formed, as shown in TEM images as well as monitored by photoluminescence spectroscopy (PL). Man functionalized SiNPs can target cancerous cells. Visualization imaging of SiNPs in MCF-7 human breast cancer cells shows the fluorescence is distributed throughout the cytoplasm of these cells.


Falls in African American and white community-dwelling elderly residents.
Few studies have examined the relationship of race to falls. This study evaluated the association between potential risk factors and falls in a representative sample of 1049 African American and 1947 white participants of the second in-person wave of the Duke Established Populations for Epidemiologic Studies of the Elderly. Information about sociodemographic characteristics, health-related behaviors, health status, visual function, and drug use was determined during baseline in-home interviews. Three years later, falls in the previous 12 months were assessed by self-report. One or more falls occurred in 22.2% of the participants. Nearly half the fallers reported more than one fall. Multivariable analysis revealed that African Americans were less likely than whites to have any fall (adjusted odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62-0.94). Increased age and education, arthritis, diabetes, and history of broken bones were also significant (p <.05) independent risk factors for any fall. In multivariable analyses comparing those with two or more falls to those with none, again, increased age and education, arthritis, and diabetes were significant (p <.05) independent risk factors while smoking was protective. Race was not a significant predictor of multiple falls (adjusted OR 0.90, 95% CI 0.64-1.26). Similar sociodemographic characteristics and health problems appear to be important risk factors for any and multiple falls in community-dwelling African American and white elderly residents, with white elders at greater risk of one-time falls.


Stability of a modified, live panleucopenia virus stored in liquid phase.
It has been shown that a modified, live panleucopenia virus is quite stable when stored in the medium in which it was produced.


Why Do Schwann Cells Survive in the Absence of Axons?
Schwann cell precursors in embryonic nerves rely for survival on signals from the axons they associate with. A major component of this signal is β neuregulin. While it can be argued that such paracrine axonal regulation makes biological sense in embryonic nerves, such an arrangement would be problematic postnatally, since nerve damage would then lead to Schwann cell death with adverse consequences for regeneration; in fact, transection of older nerves is not accompanied by a detectable increase in Schwann cell death. Our evidence indicates that this is, at least in part, due to the ability of Schwann cells to support their own survival by autocrine circuits. These circuits are not present in Schwann cell precursors. We have identified insulin-like growth factor, neurotrophin-3 and platelet-derived growth factor-BB as components of the autocrine Schwann cell survival signal.


Before your very eyes: the value and limitations of eye tracking in medical education.
Medicine is a highly visual discipline. Physicians from many specialties constantly use visual information in diagnosis and treatment. However, they are often unable to explain how they use this information. Consequently, it is unclear how to train medical students in this visual processing. Eye tracking is a research technique that may offer answers to these open questions, as it enables researchers to investigate such visual processes directly by measuring eye movements. This may help researchers understand the processes that support or hinder a particular learning outcome. In this article, we clarify the value and limitations of eye tracking for medical education researchers. For example, eye tracking can clarify how experience with medical images mediates diagnostic performance and how students engage with learning materials. Furthermore, eye tracking can also be used directly for training purposes by displaying eye movements of experts in medical images. Eye movements reflect cognitive processes, but cognitive processes cannot be directly inferred from eye-tracking data. In order to interpret eye-tracking data properly, theoretical models must always be the basis for designing experiments as well as for analysing and interpreting eye-tracking data. The interpretation of eye-tracking data is further supported by sound experimental design and methodological triangulation.


Sindbis virus-mediated cell fusion from without is a two-step event.
The process by which Sindbis virus induces the fusion of BHK-21 cells in monolayer cultures after exposure to low pH was examined. The fusion process was found to require an exposure to low pH followed by a return to conditions closer to neutral pH. The rate at which cells fused was affected by the pH to which the monolayers were exposed, subsequent to the initial exposure to acid conditions. Virus-mediated cell fusion was not observed if the virus-cell complexes were maintained at the acid pH required for membrane fusion.


Endemic malaria: an 'indoor' disease in northern Europe. Historical data analysed.
Endemic northern malaria reached 68 degrees N latitude in Europe during the 19th century, where the summer mean temperature only irregularly exceeded 16 degrees C, the lower limit needed for sporogony of Plasmodium vivax. Because of the available historical material and little use of quinine, Finland was suitable for an analysis of endemic malaria and temperature. Annual malaria death frequencies during 1800-1870 extracted from parish records were analysed against long-term temperature records in Finland, Russia and Sweden. Supporting data from 1750-1799 were used in the interpretation of the results. The life cycle and behaviour of the anopheline mosquitoes were interpreted according to the literature. Malaria frequencies correlated strongly with the mean temperature of June and July of the preceding summer, corresponding to larval development of the vector. Hatching of imagoes peaks in the middle of August, when the temperature most years is too low for the sporogony of Plasmodium. After mating some of the females hibernate in human dwellings. If the female gets gametocytes from infective humans, the development of Plasmodium can only continue indoors, in heated buildings. Northern malaria existed in a cold climate by means of summer dormancy of hypnozoites in humans and indoor transmission of sporozoites throughout the winter by semiactive hibernating mosquitoes. Variable climatic conditions did not affect this relationship. The epidemics, however, were regulated by the population size of the mosquitoes which, in turn, ultimately was controlled by the temperatures of the preceding summer.


Relationships of hHpr1/p84/Thoc1 expression to clinicopathologic characteristics and prognosis in non-small cell lung cancer.
Nuclear matrix proteins (NMPs) are important diagnostic and prognostic markers in various human cancers. The hHpr1/p84/Thoc1 protein, a key NMP, resides in the nuclear matrix and is involved in the human TREX complex, which is required for regulation of transcription elongation, pre-RNA splicing, and mRNA export of a subset of human genes. Depletion of hHpr1/p84/Thoc1 decreases growth rates in multiple cancer cell lines, and the expression levels of hHpr1/p84/Thoc1 are strongly associated with tumor size and aggressiveness of several human cancers. Little is known about the expression of this protein in human non-small cell lung cancer (NSCLC) and its association with patients' clinicopathologic characteristics and prognosis. We evaluated hHpr1/p84/Thoc1 expression in 133 NSCLC patients by immunohistochemistry of tissue microarrays using paraffin-embedded tumor tissue and we confirmed the tissue staining by Western blot analysis. The prognostic significance of hHpr1/p84/Thoc1 expression in tumor tissue was assessed by the Cox proportional hazards regression model. hHpr1/p84/Thoc1 expression was found in 51% of patients, and was more prevalent in males than females (59% vs 43%, p = 0.07) and in blacks than whites (91% vs 48%, p = 0.009). In survival analysis, hHpr1/p84/Thoc1 expression appeared to be weakly associated with elevated risk of death among patients with stage I tumors (RR = 1.53, 95% CI = 0.85-2.77, p = 0.16), squamous cell carcinomas (RR = 1.75, 95% CI = 0.73-4.21, p = 0.21), and family histories of lung cancer (RR = 1.55, 95% CI = 0.81-2.97, p=0.18), although none of these associations was statistically significant. Thus elevated expression of hHpr1/p84/Thoc1 is common in NSCLC and may have prognostic significance in subgroups of patients. Further studies with larger sample size are needed to elucidate the role of this critical nuclear matrix protein in NSCLC prognosis.


The National Breast and Cervical Cancer Early Detection Program: report on the first 4 years of mammography provided to medically underserved women.
We describe results from 284,503 mammographic examinations and associated diagnostic workups provided to medically underserved women in an ongoing nationwide breast cancer early detection program. We report the results of mammographic examinations and diagnostic workups on 230,143 medically underserved women 40 years old or older who underwent at least one mammographic examination from July 1991 through June 1995. Mammograms were obtained in hundreds of mammography and clinical facilities throughout the United States, including community health centers, health department clinics, private practitioners' offices, university based facilities, and mobile mammography units. Our analysis included rates of mammograms with abnormal findings (reported according to the categories of the American College of Radiology Breast Imaging Reporting and Data System), breast cancer detection rates, numbers of diagnostic procedures performed, stage and size distribution of breast cancers, and positive predictive value of mammograms and biopsies with abnormal findings--all presented according to screening round and 10-year age intervals. Mammograms with abnormal findings constituted 5% of mammograms in the first round and 4% in subsequent rounds, both proportions declining by approximately one third from the youngest (40-49 years) to the oldest (70 years and older) age group. Breast cancer detection rates per 1000 mammographic examinations were 5.1 for the first round and 2.0 for subsequent rounds; from the youngest to the oldest age group, the first-round rates doubled and the subsequent-round rates tripled. Early-stage cancers accounted for 54% of first-round cancers and 81% of subsequent-round cancers. Percentage of invasive cancers at least 2 cm in size declined from 51% in the first round to 33% in subsequent rounds: however, we found little change in the proportion of lesions smaller than 1 cm. Positive predictive values declined from 9.5 cancers per 100 mammograms with abnormal findings in the first round to 5.6 cancers per 100 mammograms with abnormal findings in the subsequent rounds. A large nationwide breast cancer early detection program conducted through hundreds of diverse facilities has provided results that, although not a statistically representative sample of mammography services, are probably the best available characterization of the current state of breast cancer screening practices as they actually occur in the 1990s in the United States. These results should be useful to clinicians, researchers, and public health personnel in counseling patients, planning new studies, and improving efforts to control breast cancer.


Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences.
We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.


Genetic dissection of the initiation of the infection process and nodule tissue development in the Rhizobium-pea (Pisum sativum L.) symbiosis.
Twelve non-nodulating pea (Pisum sativum L.) mutants were studied to identify the blocks in nodule tissue development. In nine, the reason for the lack of infection thread (IT) development was studied; this had been characterized previously in the other three mutants. With respect to IT development, mutants in gene sym7 are interrupted at the stage of colonization of the pocket in the curled root hair (Crh- phenotype), mutants in genes sym37 and sym38 are blocked at the stage of IT growth in the root hair cell (Ith- phenotype) and mutants in gene sym34 at the stage of IT growth inside root cortex cells (Itr- phenotype). With respect to nodule tissue development, mutants in genes sym7, sym14 and sym35 were shown to be blocked at the stage of cortical cell divisions (Ccd- phenotype), mutants in gene sym34 are halted at the stage of nodule primordium (NP) development (Npd- phenotype) and mutants in genes sym37 and sym38 are arrested at the stage of nodule meristem development (Nmd- phenotype). Thus, the sequential functioning of the genes Sym37, Sym38 and the gene Sym34 apparently differs in the infection process and during nodule tissue development. Based on these data, a scheme is suggested for the sequential functioning of early pea symbiotic genes in the two developmental processes: infection and nodule tissue formation.


Weightlifting exercise and the size-weight illusion.
In the size-weight illusion (SWI), large objects feel lighter than equally weighted small objects. In the present study, we investigated whether this powerful weight illusion could influence real-lift behavior-namely, whether individuals would perform more bicep curls with a dumbbell that felt subjectively lighter than with an identically weighted, but heavier-feeling, dumbbell. Participants performed bicep curls until they were unable to continue with both a large, light-feeling 5-lb dumbbell and a smaller, heavy-feeling 5-lb dumbbell. No differences emerged in the amounts of exercise that participants performed with each dumbbell, even though they felt that the large dumbbell was lighter than the small dumbbell. Furthermore, in a second experiment, we found no differences in how subjectively tired participants felt after exercising for a set time with either dumbbell. We did find, however, differences in the lifting dynamics, such that the small dumbbell was moved at a higher average velocity and peak acceleration. These results suggest that the SWI does not appear to influence exercise outcomes, suggesting that perceptual illusions are unlikely to affect one's ability to persevere with lifting weights.


Central bombesin activates the hypothalamic-pituitary-adrenal axis. Effects on regional levels and release of corticotropin-releasing hormone and arginine-vasopressin.
While corticotropin-releasing hormone (CRH) is a primary regulator of the hypothalamic-pituitary-adrenal (HPA) axis, the mechanism(s) triggering the release of this corticotropin (ACTH) secretagogue remains unknown. Stressful and appetitive events evoke the release of not only CRH but also of bombesin (BN)-like peptides. Furthermore, CRH antagonists attenuate the endocrine and behavioral effects of BN, suggesting that BN-like peptides may mediate their effects via CRH release. An initial (mapping) study revealed that centrally administered BN (0.25 or 0.5 microg i.c.v.) increased circulating corticosterone and ACTH levels and decreased immunoreactive (ir)-CRH at the nucleus of the solitary tract, ventromedial (VMH) and anterior hypothalamic nuclei, and the central amygdaloid nucleus. Whereas BN treatment decreased ir-vasopressin (AVP) at the VMH, it elevated levels of this peptide in the hypothalamic paraventricular and median eminence/arcuate (Me/Arc) regions. Dynamic, in vivo release experiments (using push-pull perfusion) revealed that BN evoked the release of ir-CRH and ir-AVP from the Me/Arc and increased interstitial levels of these secretagogues at the anterior pituitary. These results suggest that BN-like peptides may regulate certain hypothalamic and extrahypothalamic circuits, including the HPA axis, by affecting regional utilization of ir-CRH and ir-AVP, and/or by provoking the release of these peptides at the Me/Arc, thus increasing their availability downstream at the anterior pituitary and increasing circulating ACTH and corticosterone levels.


Comparison of clavicular hook plate with and without coracoclavicular suture fixation for acute acromioclavicular joint dislocation.
The aim of this study was to compare the clinical and radiographic outcomes of clavicular hook plate fixation with and without coracoclavicular (CC) tape augmentation for the treatment of acute unstable AC dislocation. We treated 47 patients (31 men and 16 women; mean age: 47 years (range, 21-81)) with unstable acute AC dislocations (Rockwood III-V) and divided them into two groups according to the treatment modality, with hook plate fixation (hook plate group) or hook plate plus CC tape augmentation (combined group). We assessed radiologic findings, such as subacromial osteolysis and AC osteoarthritis. We also evaluated the clinical outcomes using a visual analogue scale (VAS) for pain, as well as the University of California at Los Angeles (UCLA) Shoulder Rating Scale and the American Shoulder and Elbow Surgeons (ASES) Shoulder Score. We found that the combined group had less subacromial osteolysis upon radiography, although the CC distance was similar in both groups (119 ± 29.7% of contralateral side CC distance in hook plate group versus 119 ± 34.8% in the combined group, p = 0.77). Compared with the hook plate group, the combined group had a lower VAS score (4.5 ± 2.3 in hook plate group versus 2.3 ± 1.4 in the combined group, p < 0.001), better UCLA scores (19.9 ± 4.9 in hook plate group versus 27.2 ± 4.0 in the combined group, p < 0.001) as well as better ASES scores (51.9 ± 17.8 in hook plate group versus 73.8 ± 13.1 in the combined group, p < 0.001) at 3 and 6 months after surgery. Hook plate fixation plus CC tape augmentation may prevent subacromial osteolysis and yield better short-term functional outcomes. Level III, Therapeutic Study.


Orbital Floor Fractures.
The orbital bones are thin and exposed, making the orbital walls vulnerable to fractures. The floor of the orbit is the weakest portion of this 4-sided pyramid structure. Blunt force trauma is the primary mechanism of injury in young men between the ages of 18 and 30 years. Computerized tomography is the primary imaging technique to diagnose orbital fractures. Conservative versus surgical management is determined by maxillofacial and ophthalmology specialists.


Objective and subjective evaluation of a redesigned corridor environment in a psychiatric hospital.
This study examined the impact of redesigning a corridor space within a psychiatric hospital on the behaviour of patients with dementia. In addition, patient and staff perceptions of the redesigned corridor were assessed. Data were collected through an observational tool (behavioural mapping) and a specifically design questionnaire. The findings suggest a positive impact of the redesigned corridor on patient behaviour and that patients and staff perceived the change to the environment differentially. These results are discussed in relation to theoretical explanations of the importance of the health care environment and design for dementia.


Mitochondrial Energy Metabolism and Thyroid Cancers.
Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.


[Upper digestive haemorrhage due to Mallory-Weiss syndrome. Role of endoscopic sclerotherapy].
Although Mallory-Weiss syndrome is responsible for between 0.5 and 17% of the cases of upper digestive haemorrhage, the information existing on the endoscopic treatment of this syndrome is scarce. We made a retrospective study of 71 patients with haemorrhage due to Mallory-Weiss syndrome, dividing them into two groups according to the treatment they had received (medical or medical-endoscopic). Hence, 60 patients (30 with clean laceration, 9 with signs of prior haemostasia and 21 with fresh clotting) had been treated with procinetics and/or antisecretories alone, while the 11 remaining (8 with active haemorrhage, 2 with visible vessel and 1 with fresh clotting) had also received endoscopic treatment with sclerotherapy. We compared the clinical and analytical characteristics and the evolution of both groups of patients, analysing the data by means of the Mann-Whitney U and the chi 2 test. The endoscopic sclerosis group showed maelenas more frequently and more severe analytical data of haemorrhage (p<0.01). Endoscopic sclerosis brought initial control of the haemorrhage in all the patients, with a low index of haemorrhage relapse, similar to the group receiving exclusively medical treatment. In our series, the patients with Mallory-Weiss syndrome with active bleeding or visible vessel presented a haemorrhage with a greater clinical and analytical repercussion. In this group of patients, endoscopic sclerotherapy controlled the haemorrhage and/or prevented rebleeding, in the absence of complications.


Adventitial vessel growth and progenitor cells activation in an ex vivo culture system mimicking human saphenous vein wall strain after coronary artery bypass grafting.
Saphenous vein graft disease is a timely problem in coronary artery bypass grafting. Indeed, after exposure of the vein to arterial blood flow, a progressive modification in the wall begins, due to proliferation of smooth muscle cells in the intima. As a consequence, the graft progressively occludes and this leads to recurrent ischemia. In the present study we employed a novel ex vivo culture system to assess the biological effects of arterial-like pressure on the human saphenous vein structure and physiology, and to compare the results to those achieved in the presence of a constant low pressure and flow mimicking the physiologic vein perfusion. While under both conditions we found an activation of Matrix Metallo-Proteases 2/9 and of microRNAs-21/146a/221, a specific effect of the arterial-like pressure was observed. This consisted in a marked geometrical remodeling, in the suppression of Tissue Inhibitor of Metallo-Protease-1, in the enhanced expression of TGF-β1 and BMP-2 mRNAs and, finally, in the upregulation of microRNAs-138/200b/200c. In addition, the veins exposed to arterial-like pressure showed an increase in the density of the adventitial vasa vasorum and of cells co-expressing NG2, CD44 and SM22α markers in the adventitia. Cells with nuclear expression of Sox-10, a transcription factor characterizing multipotent vascular stem cells, were finally found in adventitial vessels. Our findings suggest, for the first time, a role of arterial-like wall strain in the activation of pro-pathologic pathways resulting in adventitial vessels growth, activation of vasa vasorum cells, and upregulation of specific gene products associated to vascular remodeling and inflammation.


Characterization of myelin basic protein catabolism products in the cerebrospinal fluid from multiple sclerosis, stroke and head injury patients.
Polyclonal antisera were raised to thirteen synthetic peptides corresponding to different regions of the human myelin basic protein molecule. These were used with a radioligand of human myelin basic protein to establish region-specific assays for the detection of myelin basic protein catabolism products in spinal fluid. The limits of detection for the various assays ranged from 0.2 to 2.5 ng/ml human myelin basic protein. These assays were used to search for evidence of myelin basic protein-like immunoreactivity in spinal fluids from multiple sclerosis, stroke and head injury patients. Generally, those assays specific for regions in the centre of the molecule measured the largest amounts of material and this was true for all the samples regardless of aetiology. It would appear from the results of this preliminary study that any disease specific pattern of peptides is superimposed on to a strong general background pattern. The simultaneous detection in individual spinal fluid samples of material cross-reactive with anti-peptide antibodies raised to multiple different regions of myelin basic protein is strong evidence that the material is in fact derived from myelin basic protein. The region-specific antisera described in this study should prove valuable reagents for the continued study of myelin basic protein catabolism.


Risk score for predicting in-hospital/30-day mortality for patients undergoing valve and valve/coronary artery bypass graft surgery.
Risk scores are simplified linear formulas for predicting mortality or other adverse outcomes at the bedside without personal digital assistants or calculators. Although risk scores are available for valve surgery, they do not predict short-term mortality (within 30 days of surgery) after hospital discharge. New York's Cardiac Surgery Reporting System 2007 to 2009 data were matched to vital statistics data to identify valve surgery with and without concomitant coronary artery bypass graft (CABG) surgery deaths occurring in the index admission or within 30 days after the procedure in any location. Risk scores were created to easily predict these outcomes by modifying more complicated logistic regression models. There were 13,455 isolated valve surgery patients and 8,373 valve/CABG surgery patients in the study. The respective in-hospital/30-day mortality rates were 4.03% and 6.60%. There are 11 risk factors comprising the isolated valve surgery score, with risk factor scores ranging from 1 to 8, and the highest observed total score is 28. There are 14 risk factors comprising the valve/CABG surgery score, with risk factor scores ranging from 1 to 6, and the highest observed total score is 19. The scores accurately predicted mortality in 2007 to 2009 as well as in 2004 to 2006, and were strongly correlated with complications and length of stay. The risk scores that were developed provide quick and accurate estimates of patients' chances of short-term mortality after cardiac valve surgery.