Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases?
To evaluate the influence of the response to preoperative chemotherapy, especially tumor progression, on the outcome following resection of multiple colorectal liver metastases (CRM). Hepatic resection is the only treatment that currently offers a chance of long-term survival, although it is associated with a poor outcome in patients with multinodular CRM. Because of its better efficacy, chemotherapy is increasingly proposed as neoadjuvant treatment in such patients to allow or to facilitate the radicality of resection. However, little is known of the efficacy of such a strategy and the influence of the response to chemotherapy on the outcome of hepatic resection. We retrospectively analyzed the course of 131 consecutive patients who underwent liver resection for multiple (> or =4) CRM after systemic chemotherapy between 1993 and 2000, representing 30% of all liver resections performed for CRM in our institution during that period. Chemotherapy included mainly 5-fluorouracil, leucovorin, and either oxaliplatin or irinotecan for a mean of 9.8 courses (median, 9 courses). Patients were divided into 3 groups according to the type of response obtained to preoperative chemotherapy. All liver resections were performed with curative intent. We analyzed patient outcome in relation to response to preoperative chemotherapy. There were 58 patients (44%) who underwent hepatectomy after an objective tumor response (group 1), 39 (30%) after tumor stabilization (group 2), and 34 (26%) after tumor progression (group 3). At the time of diagnosis, mean tumor size and number of metastases were similar in the 3 groups. No differences were observed regarding patient demographics, characteristics of the primary tumor, type of liver resection, and postoperative course. First line treatments were different between groups with a higher proportion of oxaliplatin- and/or irinotecan-based treatments in group 1 (P < 0.01). A higher number of lines of chemotherapy were used in group 2 (P = 0.002). Overall survival was 86%, 41%, and 28% at 1, 3, and 5 years, respectively. Five-year survival was much lower in group 3 compared with groups 1 and 2 (8% vs. 37% and 30%, respectively at 5 years, P < 0.0001). Disease-free survival was 3% compared with 21% and 20%, respectively (P = 0.02). In a multivariate analysis, tumor progression on chemotherapy (P < 0.0001), elevated preoperative serum CA 19-9 (P < 0.0001), number of resected metastases (P < 0.001), and the number of lines of chemotherapy (P < 0.04), but not the type of first line treatment, were independently associated with decreased survival. Liver resection is able to offer long-term survival to patients with multiple colorectal metastases provided that the metastatic disease is controlled by chemotherapy prior to surgery. Tumor progression before surgery is associated with a poor outcome, even after potentially curative hepatectomy. Tumor control before surgery is crucial to offer a chance of prolonged remission in patients with multiple metastases.


Low expression of lymphocyte function-associated antigen (LFA)-1 and LFA-3 adhesion molecules is a common trait in Burkitt's lymphoma associated with and not associated with Epstein-Barr virus.
Lymphocyte function-associated antigens 1 and 3 (LFA-1, LFA-3) and intercellular adhesion molecule 1 (ICAM-1) are cell surface adhesion molecules necessary for immune processes requiring intercellular contact. It was recently proposed that malignant Burkitt's lymphoma cells (BL) may escape from immunosurveillance through the downregulation of LFA-1 (CD11a/CD18) or LFA-3 (CD58) and ICAM-1 (CD54) molecules. Expression of these three adhesion antigens was investigated in 19 BL lines. LFA-1 or LFA-3 expression was found to be absent or low in 8 of 11 Epstein-Barr virus (EBV) genome positive BL, but strongly expressed on all nonmalignant EBV genome positive lymphoblastoid cell lines (LCL). Negative or weak expression of LFA-1 and LFA-3 was also observed in 7 of 8 EBV genome negative BL. ICAM-1 was found to be expressed on the cell surface of the majority of BL lines. BL lines growing as individual cells did not express LFA-1, whereas clump-forming BL lines expressed this marker involved in B-cell homotypic aggregation. Expression of LFA-1 and LFA-3 was induced on in vitro infection of EBV-negative BL cells with the immortalizing EBV strain B95-8, and weakly with the nonimmortalizing EBV strain P3HR1. EBNA2 and LMP, two EBV encoded proteins expressed in LCL and in BL infected with B95-8 (BL/B95-8), are not expressed in P3HR1 infected BL cells (BL/P3HR1). Stable expression of EBNA2 after gene transfer in a BL/P3HR1 cell line did not restore the level of LFA-1 and LFA-3 found on BL/B95-8 cells. In EBV-positive BL cells expressing LFA-1 and LFA-3, LMP was found coexpressed, supporting the recent finding of the role of LMP in B-cell adhesion receptor activation. Consequently, diminished LFA-1 and LFA-3 expression appears to be a common characteristic of numerous EBV-positive BL as well as EBV-negative BL. These findings are discussed in the framework of BL pathogenesis.


CT imaging vs. traditional radiographic imaging for evaluating Harris Lines in tibiae.
This paper is the first to systematically investigate computer tomography (CT) images vs. ordinary flat plane radiography for evaluating Harris Lines (HL) on tibiae. Harris Lines are traditionally investigated using radiographic images and recorded as either present or absent, or by counting the number of HL. Seventy-four pairs of human sub-adult and adult archaeological tibiae were used in this study. Both image methods were tested for intra- and inter-observer agreement and the methods were then compared. Analysis was performed with the tibiae divided into younger (n = 19) and older sub-adults (n = 26) and adults (n = 29), as well as all tibiae combined (n = 74). This study found that the intra- and inter-observer agreement was very similar for each method, but both image methods performed less well for counting the number of HL. Direct comparison between CT images and radiographic images showed good agreement for presence or absence of HL and less agreement for counting HL. There appeared to be no systematic pattern for dividing the material according to bone length (and thereby age). Overall, this paper concludes that the performance of CT images is comparable to traditional flat plane radiography for evaluating HL on archaeological dry bone specimens of tibiae. Further, due to the lower performance of counting the number of HL, it appears advisable to only record the presence or absence of HL rather than counting the number of HL.


Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.
The Birt-Hogg-Dubé syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dubé syndrome, in 13 Birt-Hogg-Dubé haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5-31.6) and approximately 9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4-392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dubé syndrome. The Birt-Hogg-Dubé syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas.


Work increases the incidence of carpal tunnel syndrome in the general population.
The purpose of this study was to estimate the incidence of carpal tunnel syndrome (CTS) in a general population according to employment status and to assess the proportion of cases attributable to work. CTS occurring in patients aged 20-59 years living in the French Maine and Loire region were included prospectively from 2002 to 2004. Medical and occupation history was gathered by mailed questionnaire. Incidence rates of CTS and relative risks (RRs) of CTS were computed in relation to employment status. The attributable fractions of risk of CTS to work among the exposed persons (AFEs) were calculated. A total of 1168 patients (819 women, 349 men) were included during the 3-year period. The mean incidence rate of CTS per 1000 person-years was higher in employed than unemployed persons (1.7 vs. 0.8 in women and 0.6 vs. 0.3 in men). The excess risk of CTS was statistically significant for male (RR 4.2) and female (RR 3.0) blue-collar workers and female lower-grade white-collar workers (RR 2.5). The AFE to work in general was 47% (95% confidence interval: 39-54) in women. AFEs reached higher values in female blue-collar workers [67% (65-68)] and lower-grade services, sales, and clerical white-collar workers [61% (57-64)]. The AFE in male blue-collar workers was 76% (72-80). These data show a higher incidence of CTS in the working than the non-working population and suggest that a substantial proportion of CTS cases diagnosed in lower-grade white-collar and blue-collar workers are attributable to work.


STformer: Spatial-Temporal Transformer for early Warning of Unplanned Extubation in ICU.
Patients' Unplanned Extubation (UEX) is dangerous in the intensive care units (ICU), it is necessary to make early warning of UEX. However, the low fine-grained action of UEX and complexity of ICU environment make early warning a great challenging by using RGB video data. To address this issue, we propose a novel lightweight Spatial-Temporal Transformer (STformer) for early warning of patients' UEX action in the ICU. Specially, the SlowFast is used to extract patient's spatial-temporal features initially. Then, in order to improve the representation of features, we introduce spatial attention to enhance the spatial representation of fine-grained actions, and capture the long-term dependency of motions through temporal attention. Finally, a spatial-temporal joint attention is used to reconstruct and strengthen spatial and temporal information. Experiment results illustrate state-of-the-art performance of our STformer on ICU monitory datasets. While ensuring the accuracy of early warning, the computational complexity of STformer are also light.


Quantitation of propriospinal fibers in the tract of Lissauer of the rat.
The present study uses a spinal cord isolation procedure to remove extrinsic axons but leave intrinsic axons intact. The isolation is done by sectioning the spinal cord in two places and then cutting all dorsal roots between the two sections. The axons that survive the isolation procedure are thought to be propriospinal axons. Following isolation, approximately one-third of the axons in sacral tracts of Lissauer in the rat survive. Thus approximately one-third of the axons in sacral tracts of Lissauer in the rat are propriospinal. Proportionately more myelinated than unmyelinated axons are lost. There are approximately equal numbers of surviving axons in the medial as opposed to the lateral part of the tract. This implies that there is, as yet, no morphological basis for dividing the tract into medial and lateral halves. The fact that the number of propriospinal axons in the tract of Lissauer has been quantitated offers more precision in our thinking about the organization of the dorsal horn.


Predictors of functional deterioration in Chinese patients with psoriatic arthritis: a longitudinal study.
Psoriatic arthritis (PsA) disease activities at baseline may determine physical function over time. There is no longitudinal data on course of physical function in PsA patients from Asia. We aim to describe variables associated with a deterioration of physical function in PsA in Chinese over a 6-year period. 125 consecutive patients with PsA fulfilled the CASPAR criteria from a rheumatology outpatient center were recruited to give sociodemographic and clinical data in 2006 to 2008. Follow up interviews were conducted in 2012 to 2013 to assess physical function using Health Assessment Questionnaire (HAQ). Regression models were constructed to determine baseline variables that predict physical function on follow up. A total of 97 patients completed the follow up survey, with mean follow up time of 6.2 (±0.7) years, response rate 77.6%. PsA patients had poor physical function and health related quality of life (HRQoL) compared to normal population. There were 33% who improved in disability status and 41.2% had persistent minimal disability by HAQ categories (HAQ 0-0.49) over time. There were 14.4% of the patients who had persistent moderate disability (HAQ 0.5-1.50) and 10.3% had deterioration in disability status. There were 17.5% of patients who had deterioration in physical function as defined by an increment of HAQ score of more than 0.2 at follow up survey. Age, physical function at baseline and the number of damaged joint were significantly related HAQ at follow up. Chinese patients with PsA had had poor physical function and quality of life. One fifth of patient experienced deterioration of physical function over time. Joint damage and baseline physical function were important factors associated with poor physical function in PsA over time.


A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression.
While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.


A Single-institution Study on Predictors of Short-term Progression from Mild Cognitive Impairment in Parkinson's Disease to Parkinson's Disease with Dementia.
Patients with non-demented Parkinson's disease (PD) sometime have mild cognitive impairment (MCI), and mild cognitive impairment in Parkinson's disease (PD-MCI) may convert to Parkinson's disease with dementia (PDD) within several years. Cognitive impairment also occurs in the early stages of the disease, gradually progressing to lower quality of life and instrumental activities of daily living. It is important to elucidate the predictors of progression from PD-MCI to PDD via longitudinal studies. This was a single center, case-control study. We analysed data from 49 patients with PD-MCI diagnosed as level I using the Movement Disorder Society PD-MCI criteria at baseline who had completed 1.5 years of follow-up. We defined patients who progressed to PDD as patients with progressive PD-MCI and patients who did not progress to PDD as patients with non-progressive PD-MCI. Depression, apathy, sleep disorders, constipation, light-headedness, hallucinations, impulse control disorders (ICDs) and impulsive-compulsive behaviors (ICBs) at baseline were statistically analysed as predictors of progression. Of the 49 PD-MCI patients, 33 did not convert to PDD (non-progressive PD-MCI), and 16 converted to PDD (progressive PD-MCI). The Mini-Mental State Examination (MMSE) score, light-headedness and ICDs were elucidated as predictors of progressive PD-MCI via a multivariate logistic regression model. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each item were MMSE score, OR 0.324, 95% CI 0.119-0.882, P = 0.027; light-headedness, OR 27.665, 95% CI 2.263-338.185, P= 0.009; and ICDs, OR 53.451, 95% CI 2.298-291.085, P = 0.010. Cognitive function, ICDs and light-headedness may be risk factors for the development of PDD in PD-MCI patients.


Acute resistance exercise attenuates fasting and postprandial triglyceridemia in women by reducing triglyceride concentrations in triglyceride-rich lipoproteins.
A single bout of endurance exercise lowers fasting and postprandial triglyceride (TG) concentrations in both men and women, by reducing TG in triglyceride-rich lipoproteins (TRLs). The effect of resistance exercise on TRL-TG metabolism is not known; previous studies only measured total plasma TG concentrations and provide conflicting results. Furthermore, none has specifically examined women. We therefore sought to evaluate the effect of a single bout of resistance exercise on TRL-TG metabolism in women. We measured the concentrations of TG in total plasma and TRLs in the fasting state and during an oral fat tolerance test in five healthy untrained women (age: 32 ± 5 years; body mass index: 21.5 ± 1.7 kg/m(2); peak oxygen consumption: 31 ± 4 mL/kg min) in the morning, on two separate occasions: once after a single ~95-min bout of moderate-intensity whole-body resistance exercise (energy expenditure: 2.9 ± 0.1 MJ) and once after an equivalent period of rest, on the preceding afternoon. Fasting plasma TG and TRL-TG concentrations were 22 ± 12 and 40 ± 21% lower, respectively, and postprandial plasma TG and TRL-TG areas-under-the-curve were 24 ± 13 and 27 ± 10% lower, respectively, after exercise than rest (all P values <0.05). Effect sizes ranged from -0.52 to -0.90. Non-TRL-TG concentrations in the fasting and postprandial states were not different between trials (P > 0.60). We conclude that a single bout of resistance exercise attenuates fasting and postprandial triglyceridemia in women by reducing TRL-TG concentrations.


Correlates of the Militant Extremist Mindset.
This study aimed to examine bright- and dark-side personality, personal beliefs (religion and politics) and self-evaluation correlates of beliefs in the Militant Extremist Mindset (MEM). In all, 506 young adults completed various self-report measures in addition to the three-dimensional MEM questionnaire. The measures included short measures of the Big Five traits, Self-Monitoring, Self-Evaluation and Personality Disorders, as well as demographic questions of how religious and politically liberal participants were. The Proviolence, Vile World, and Divine power mindsets showed varying correlates, with no consistent trend. Stepwise regressions showed that the demographic, personality and belief factors accounted for between 14% (Vile World) and 54% (Divine Power) of the variance, There were many differences between the results of three mindset factors, but personality disorder scores remained positive predictors of all three. The Vile World mindset was predicted by religiousness, liberalism, personality disorder scores and negative self-monitoring, but not personality traits. Religiousness had a contribution to all subscales and predicted the vast majority of the Divine Power mindset with smaller relationships with personality and personality disorders. Proviolence was predicted by the majority personality measures and sex.


Differential effects of testosterone and TGF-β3 on endocytic vesicle-mediated protein trafficking events at the blood-testis barrier.
The intricate interaction between protein endocytosis, transcytosis, recycling and endosome- or ubiquitin-mediated protein degradation determines the junction integrity in epithelial cells including Sertoli cells at the blood-testis barrier (BTB). Studies have shown that androgens and cytokines (e.g., TGF-β3) that are known to promote and disrupt BTB integrity, respectively, accelerate protein endocytosis at the BTB. We hypothesized that testosterone-induced endocytosed proteins are transcytosed and recycled back to the Sertoli cell surface, whereas cytokine-induced endocytosed proteins are degraded so that androgens and cytokines have opposing effects on BTB integrity. Herein, we report that both testosterone and TGF-β3 induced the steady-state level of clathrin, an endocytic vesicle protein. Testosterone and TGF-β3 also induced the association between internalized occludin (a BTB integral membrane protein) and clathrin, as well as early endosome antigen-1 (EEA-1). Interestingly, testosterone, but not TGF-β3, also induced the levels of proteins that regulate protein transcytosis (e.g., caveolin-1) and recycling (e.g., Rab11), and their association with internalized occludin and N-cadherin from the cell surface. In contrast, TGF-β3, but not testosterone, induced the level of ubiquitin-conjugating enzyme E2 J1 (Ube2j1), a protein crucial to the intracellular protein degradation pathway, and its association with internalized occludin. Based on these findings and recent reports in the field, we hypothesize that the concerted effects of testosterone and TGF-β3 likely facilitate the transit of preleptotene spermatocytes at the BTB while maintaining the immunological barrier in that testosterone induces the assembly of "new" tight junction (TJ)-fibrils below migrating spermatocytes via protein transcytosis and recycling before cytokines induce the disassembly of "old" TJ-fibrils above spermatocytes via endocytic vesicle-mediated degradation of internalized proteins. This thus provides a unique mechanism in the testis to facilitate the transit of preleptotene spermatocytes, many of which are connected in "clones" via cytoplasmic bridges, at the BTB while maintaining the immunological barrier during stage VIII of the seminiferous epithelial cycle of spermatogenesis.


Human Butyrylcholinesterase Mutants for (-)-Cocaine Hydrolysis: A Correlation Relationship between Catalytic Efficiency and Total Hydrogen Bonding Energy with an Oxyanion Hole.
A combined computational and experimental study has been carried out to explore and test a quantitative correlation relationship between the relative catalytic efficiency (RCE) of human butyrylcholinesrase (BChE) mutant-catalyzed hydrolysis of substrate (-)-cocaine and the total hydrogen bonding energy (tHBE) of the carbonyl oxygen of the substrate with the oxyanion hole of the enzyme in the modeled transition-state structure (TS1), demonstrating a satisfactory linear correlation relationship between ln(RCE) and tHBE. The satisfactory correlation relationship has led us to computationally predict and experimentally confirm new human BChE mutants that have a further improved catalytic activity against (-)-cocaine, including the most active one (the A199S/F227S/S287G/A328W/Y332G mutant) with a 2790-fold improved catalytic efficiency (kcat/KM = 2.5 × 109 min-1 M-1) compared to the wild-type human BChE. Compared to the reference mutant (the A199S/S287G/A328W/Y332G mutant) tested in the reported clinical development of an enzyme therapy for cocaine dependence treatment, this new mutant (with a newly predicted additional F227S mutation) has an improved catalytic efficiency against (-)-cocaine by ∼2.6-fold. The good agreement between the computational and experimental ln(RCE) values suggests that the obtained correlation relationship is robust for computational prediction. A similar correlation relationship could also be explored in studying BChE or other serine hydrolases/esterases with an oxyanion hole stabilizing the carbonyl oxygen in the rate-determining reaction step of the enzymatic hydrolysis of other substrates.


Microbial load of umbilical cord blood Ureaplasma species and Mycoplasma hominis in preterm prelabor rupture of membranes.
To evaluate Ureaplasma species and M. hominis DNA in the umbilical cord blood and its correlation with its microbial load in the amniotic fluid, as a measure of microbial burden in fetal inflammatory response and neonatal outcome in pregnancies complicated by preterm prelabor rupture of membranes (pPROM). A retrospective study of 158 women with singleton pregnancies complicated by pPROM between 24(0/7) and 36(6/7) weeks was conducted. Amniotic fluid was obtained from all women by transabdominal amniocentesis, and umbilical cord blood was obtained by venipuncture from umbilical cords immediately after the delivery of the neonates. The Ureaplasma species and M. hominis DNA was quantitated using absolute quantification techniques. Ureaplasma species and M. hominis DNA was identified in 9% of the umbilical cord blood samples. No correlation between the amniotic fluid and umbilical cord blood microbial load was observed. The presence of Ureaplasma species and M. hominis DNA in the umbilical cord blood had no impact on short-term neonatal morbidity. A high microbial load of genital mycoplasma Ureaplasma species DNA in the umbilical cord in pregnancies complicated by pPROM is not associated with a high fetal inflammatory response and is therefore not associated with serious neonatal morbidity.


Increased protein sorption in poly(acrylic acid)-containing films through incorporation of comb-like polymers and film adsorption at low pH and high ionic strength.
In principle, incorporation of comb-like block copolymers in multilayer polyelectrolyte films can both increase film thickness relative to coatings containing linear polymers and provide more swollen films for increased sorption of proteins. In the absence of added salt, alternating adsorption of 5 bilayers of protonated poly(allylamine) (PAH) and comb-like poly(2-hydroxyethyl methacrylate)-graft-poly(acrylic acid) (PHEMA-g-PAA) leads to ∼2-fold thicker coatings than adsorption of PAH and linear PAA, and the difference in the thicknesses of the two coatings increases with the number of bilayers. Moreover, the (PAH/PHEMA-g-PAA)n films sorb 2- to 4-fold more protein than corresponding films prepared with linear PAA, and coatings deposited at pH 3.0 sorb more protein than coatings adsorbed at pH 5.0, 7.0, or 9.0. In fact changes in deposition pH and addition of 0.5 M NaCl to polyelectrolyte adsorption solutions alter protein sorption more dramatically than variations in the constituent polymer architecture. When deposited from 0.5 M NaCl at pH 3.0, both (PAH/PHEMA-g-PAA)5 and (PAH/PAA)5 films increase in thickness more than 400% upon adsorption of lysozyme. These films contain a high concentration of free -COOH groups, and subsequent deprotonation of these groups at neutral pH likely contributes to increased protein binding. Lysozyme sorption stabilizes these films, as without lysozyme films deposited at pH 3.0 from 0.5 M NaCl desorb at neutral pH. Films deposited at pH 9.0 from 0.5 M NaCl are more stable and also bind large amounts of lysozyme. The high binding capacities of these films make them attractive for potential applications in protein isolation or immobilization of enzymes.


One of two human lactoferrin variants exhibits increased antibacterial and transcriptional activation activities and is associated with localized juvenile periodontitis.
The iron-binding protein lactoferrin is a ubiquitous and abundant constituent of human exocrine secretions. Lactoferrin inhibits bacterial growth by sequestering essential iron and also exhibits non-iron-dependent antibacterial, antifungal, antiviral, antitumor, anti-inflammatory, and immunoregulatory activities. All of these non-iron-dependent activities are mediated by the highly charged N terminus of lactoferrin. In this study we characterized a Lys/Arg polymorphism at position 29 in the N-terminal region of human lactoferrin that results from a single nucleotide polymorphism in exon 1 of the human lactoferrin gene. We expressed cDNAs encoding both lactoferrin variants in insect cells and purified the two proteins by ion exchange chromatography. The two lactoferrin variants exhibited nearly identical iron-binding and iron-releasing activities and equivalent bactericidal activities against a strain of the gram-negative bacterium Actinobacillus actinomycetemcomitans. When tested against the gram-positive species Streptococcus mutans and Streptococcus mitis, however, lactoferrin containing Lys at position 29 exhibited significantly greater bactericidal activity than did lactoferrin containing Arg. In addition, the Lys-containing lactoferrin stimulated bovine tracheal epithelial cells to synthesize much higher levels of tracheal antimicrobial peptide mRNA than did the Arg-containing variant. A genotyping assay that distinguished between the two alleles based on a polymorphic EarI restriction site showed that the Lys and Arg alleles had frequencies of 24% and 76%, respectively, among 17 healthy human subjects, and 72% and 28%, respectively, among nine patients with localized juvenile periodontitis. Our findings suggest that these two lactoferrin variants are functionally different and that these differences may contribute to the pathogenesis of localized juvenile periodontitis.


A Sociotechnical Framework for Safety-Related Electronic Health Record Research Reporting: The SAFER Reporting Framework.
Electronic health record (EHR)-based interventions to improve patient safety are complex and sensitive to who, what, where, why, when, and how they are delivered. Success or failure depends not only on the characteristics and behaviors of individuals who are targeted by an intervention, but also on the technical characteristics of the intervention and the culture and environment of the health system that implements it. Current reporting guidelines do not capture the complexity of sociotechnical factors (technical and nontechnical factors, such as workflow and organizational issues) that confound or influence these interventions. This article proposes a methodological reporting framework for EHR interventions targeting patient safety and builds on an 8-dimension sociotechnical model previously developed by the authors for design, development, implementation, use, and evaluation of health information technology. The Safety-related EHR Research (SAFER) Reporting Framework enables reporting of patient safety-focused EHR-based interventions while accounting for the multifaceted, dynamic sociotechnical context affecting intervention implementation, effectiveness, and generalizability. As an example, an EHR-based intervention to improve communication and timely follow-up of subcritical abnormal test results to operationalize the framework is presented. For each dimension, reporting should include what sociotechnical changes were made to implement an EHR-related intervention to improve patient safety, why the intervention did or did not lead to safety improvements, and how this intervention can be applied or exported to other health care organizations. A foundational list of research and reporting recommendations to address implementation, effectiveness, and generalizability of EHR-based interventions needed to effectively reduce preventable patient harm is provided. The SAFER Reporting Framework is not meant to replace previous research reporting guidelines, but rather provides a sociotechnical adjunct that complements their use.


Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients.
To examine the relationships between central obesity, insulin resistance index, plasma insulin, growth hormone (GH), and cortisol concentrations in 90 young Chinese type 2 diabetic patients (aged 33+/-5 years) and 104 age- and sex-matched control subjects (aged 32+/-9 years). Young Chinese diabetic patients (aged <40 years) were recruited from the Prince of Wales Hospital. Blood pressure, height, weight, and waist and hip circumferences were determined. Venous blood was sampled for measurements of fasting plasma glucose, HbA1c, lipids, creatinine, insulin, GH, and cortisol. A 24-h urine was assayed for urinary albumin excretion (UAE). General and central obesity was represented by BMI and waist circumference, respectively. Insulin resistance index was estimated as a product of fasting plasma insulin and glucose concentrations. Compared with control subjects, diabetic patients were more obese, hyperglycemic, and had worse lipid profile, higher blood pressures, UAE, insulin resistance index, plasma insulin, and cortisol concentrations (all P < 0.001) but lower GH concentrations (P < 0.05). When analyzed as a whole group (n = 194), increasing quartiles of waist circumference were associated with increasing trends of insulin resistance index, plasma insulin, and cortisol concentrations (all P < 0.01) but a decreasing trend of plasma GH concentration (P < 0.05). Using stepwise multiple regression analysis, waist circumference was only associated with sex variable (being higher in men) in the control subjects. In the diabetic group, 51% of waist circumference was independently related to male sex and increased plasma insulin and cortisol concentrations as well as reduced plasma GH levels. In young Chinese type 2 diabetic patients, hyperinsulinemia, hypercortisolemia, and reduced plasma GH levels were closely associated with central obesity. Based on these findings, we postulate that maladaptive hormonal responses to rapid changes in lifestyle may have led to obesity and type 2 diabetes in these young patients. Alternatively, lifestyle-related obesity may have given rise to these hormonal changes. More studies are required to delineate the nature of these relationships.


The rich potential for education research in family medicine and general practice.
Medical education is a rapidly growing field of research, incorporating diverse disciplinary perspectives to assist physician trainees in developing the complex skills needed for practice. Education science is happening in many medical specialties; however, Family Medicine or General Practice settings have not seen a proportional share of theory-driven education research. The limited nature of education research in Family Medicine is surprising, given that there are several aspects of general practice that make it a particularly unique and interesting context to study issues of general importance to medical education, and there is a particular need for education research to further the discipline of Family Medicine. It is important that the community of medical education researchers in Family Medicine have a strong understanding and perspective on the breadth and potential impact of their work, and what this means for the training that occurs within and for the discipline. This Reflection aims to inform strategic thinking, collaboration, and innovation in medical education research as it pertains to Family Medicine. It does so by discussing four hallmarks of Family Medicine practice and outlining their independent and interactive potential for medical education research.


Faulty Executive Attention and Memory Interactions in Schizophrenia: Prefrontal Gray Matter Volume and Neuropsychological Impairment.
We hypothesized that neuropsychological disturbance in schizophrenia (SZ) may reflect faulty interactions of executive attention and episodic memory, emanating, in part, from reduced prefrontal cortex (PFC) gray matter volume. Participants with SZ (n = 84) and age-matched (n = 77) controls completed both the Wisconsin Card Sorting Test (WCST) and the Wechsler Memory Scale-Third Edition (WMS-III), used, respectively, as measures of executive attention and episodic memory. A subset of SZ (n = 27) and control (n = 17) groups also had available 3-T magnetic resonance imaging (MRI) studies of the PFC. For SZ, but not control groups, neuropsychological results indicated that executive attention interacted significantly with episodic memory, with failures of executive attention, as reflected by increased WCST perseverative errors, directly linked to poor performance on the WMS-III measure of delayed visual recall of action scenes. MRI results indicated reduced left PFC gray matter volume for SZ group, which in turn correlated significantly with their deficits in visual memory but not in executive attention. Results showed that 61% of the variance in neuropsychological performance in the SZ group was attributed to gray matter volume of left inferior prefrontal gyrus gray matter volume. PFC-mediated failure of executive attention-episodic memory interactions may represent an important mechanism in neuropsychological disturbance in SZ.


Determination of the equilibrium distibution between alcohol and aldehyde substrates when bound to horse liver alcohol dehydrogenase using magnetic resonance.
The interactions of horse liver alcohol dehydrogenase (LADH) with the rho-trifluoromethyl derivatives of benzyl alcohol, benzaldehyde, and benzoic acid have been investigated by use of 19F nuclear magnetic resonance. The aldehyde and alcohol are good substrates for the enzyme and display kinetic characteristics similar to other alcohol/aldehyde pairs. In single-turnover experiments with NADH, rho-(trifluoromethyl)benzaldehyde shows biphasic kinetics similar to those shown by other aromatic aldehydes, which led Bernhard and co-workers [Bernard, S. A., Dunn, M. F., Luisi, P. L., & Shack, P. (1970) Biochemistry 9, 185] to propose half-of-the-sites reactivity for this enzyme. Fluorine magnetic resonance demonstrates that under equilibrium conditions at 4 degrees C and pH 8.75 rho-(trifluoromethyl)benzyl alcohol binds to LADH with a dissociation constant of 1 x 10(-3) M. Addition of 1 equiv of NAD to a stoichiometric complex of LADH and the alcohol generates a discrete resonance. This resonance corresponds to the ternary complex of LADH, NAD, and alcohol with little contribution from the NADH and aldehyde ternary complex. Quantitation shows that the bound NAD-alcohol pair is favored by at least a factor of 20 over the bound NADH-aldehyde pair at equililbrium. These results are consistent with explanations for the biphasic kinetics which involve half-of-the-sites reactivity of multiple steps in the reaction of each catalytic site. These results eliminate explanations for the biphasic kinetics of this system which require this equilibrium constant to have a value near unity or those which give greatest thermodynamic stability to the heterodimer LADH [(NAD-alcohol)(NADH-aldehyde)].


Effects of milk fermented by Lactobacillus gasseri SBT2055 on adipocyte size in rats.
Despite adequate scientific evidence of the potential benefits of probiotics to human health or disease prevention, their contribution to the growth of adipose tissue remains to be established. Four-week-old male Sprague-Dawley rats were fed a diet containing skim milk (control diet) or skim milk fermented by Lactobacillus gasseri SBT2055 (LGSP diet) for 4 weeks. Their body weight gain, adipose tissue weight, adipocyte size distribution profile, blood and hepatic lipids, and serum leptin, glucose and adiponectin levels were determined. There was a significant reduction in average adipocyte size in mesenteric white adipose tissue (P = 0.004). Moreover, the rats fed the LGSP diet displayed greater numbers of small adipocytes from mesenteric and retroperitoneal adipose tissues than did those on the control diet. Whereas adiponectin concentrations did not differ between the groups, serum leptin concentrations were decreased to 32 % in the LGSP diet group compared with the control group. Concentrations of serum glucose and lipids, and liver lipids, except for the liver TAG level, were similar in the two groups. These results indicate a possible role for a fermented milk product in the regulation of adipose tissue growth.


The effects of breastfeeding on cognitive and neurological development of children at 9 years.
The effect of breastfeeding on cognitive development in the child remains controversial. The commonly observed association between breastfeeding and higher intelligence quotient (IQ) scores in children may result from the numerous confounding factors in this complex relationship. The aim of this study was to examine whether breastfeeding is associated with later differences in children's cognitive and neurological development. Secondary analysis from a 9-year follow-up study of children of 982 smokers recruited to a randomized controlled trial of anti-smoking education in pregnancy in a maternity hospital between November 1981 and October 1982; and all ex-smokers and a random 25% sample of non-smokers during the same period (total 1853 women). Cognitive and neurological development of children was assessed by psychologists in schools using the British Ability Scales and Quick Neurological Screening Test (QNST). Data on breastfeeding and factors relevant to child development were drawn from interviews with mothers at home. Main outcome measures were IQ and QNST scores. A total of 1218 (66%) children were followed up. In total, 61.6% of children were breastfed, median duration being 12 weeks. Before adjustment, breastfeeding was significantly associated with higher total, verbal and visual IQ scores in children, and increasing duration was significantly correlated with IQ scores. Total IQ was 5.49 points higher in breastfed children (P< or = 0.001), but became non-significant after adjustment. Total IQ scores were most strongly associated with maternal education, maternal age, parity, housing and chronic childhood illness. Breastfeeding was significantly associated with better QNST scores on bivariate analysis but not after adjustment. QNST scores were most strongly associated with maternal education and the child's sex. Breastfeeding was not associated with any crude IQ advantage or difference in neurological soft signs in children at 9 years. The greater IQ score associated with breastfeeding is accounted for by confounding, with maternal and socio-economic characteristics particularly important.


The Molecular Mechanisms Underlying the Hijack of Host Proteins by the 1918 Spanish Influenza Virus.
The 1918 Spanish influenza A virus (IAV) caused one of the most serious pandemics in history. The nonstructural protein 1 (NS1) of the 1918 IAV hijacks the interaction between human CrkII and JNK1. Little is, however, known about its molecular mechanism. Here, we performed X-ray crystallography, NMR relaxation dispersion experiment, and fluorescence spectroscopy to determine the structural, kinetic, and thermodynamic mechanisms underlying the hijacking of CrkII by 1918 IAV NS1. We observed that the interaction between a proline-rich motif in NS1 and the N-terminal SH3 domain of CrkII displays strikingly rapid kinetics and exceptionally high affinity with 100-fold faster kon and 3300-fold lower Kd compared to those for the CrkII-JNK1 interaction. These results provide molecular insight into the mechanism by which 1918 IAV NS1 hijacks CrkII and disrupts its interactions with critical cellular signaling proteins.


The choice of long-term anticoagulants for the pregnant patient.
The use of long-term anticoagulants in a pregnant patient poses many problems. In order to minimize the hazards for the patient and fetus the therapy must be individualized. A therapeutic regimen which calls for the use of both heparin and sodium warfarin at various intervals during gestation is discussed.


Mononuclear leukocytes preferentially bind via CD44 to hyaluronan on human intestinal mucosal smooth muscle cells after virus infection or treatment with poly(I.C).
Pathological changes in inflammatory bowel disease include an increase in intestinal mucosal mononuclear leukocytes and hyperplasia of the muscularis mucosae smooth muscle cells (M-SMCs). Because virus infections have correlated with disease flare, we tested the response of cultured M-SMCs to respiratory syncytial virus, measles virus, and the viral analogue, poly(I.C). Adhesion of U937 cells and peripheral blood mononuclear cells was used to measure the leukocyte-interactive potential of M-SMCs. Untreated M-SMCs, only minimally adhesive for leukocytes, bound U937 cells after treatment with respiratory syncytial virus or measles virus. Mononuclear leukocytes also bound to poly(I.C)-treated M-SMCs. Although both vascular cell adhesion molecule-1 mRNA and protein increased 3-4-fold in poly(I.C)-treated M-SMC cultures, U937 cell adhesion was not blocked by an anti-vascular cell adhesion molecule-1 monoclonal antibody. However, hyaluronidase digestion of poly(I.C)- or virus-treated M-SMCs dramatically reduced leukocyte adhesion ( approximately 75%). Fluorophore-assisted carbohydrate electrophoresis demonstrated a approximately 3-fold increase in surface-bound hyaluronan on poly(I.C)-treated M-SMCs compared with untreated controls. In addition, pretreatment of mononuclear cells with a blocking anti-CD44 antibody, greatly decreased adhesion to poly(I.C)-treated M-SMCs. Recognition of this virus-induced hyaluronan/CD44 mechanism of mesenchymal cell/leukocyte interaction introduces a new avenue in the research of gut inflammation.


Contralateral axillary lymph node metastasis and molecular changes in second primary breast cancer: a case report.
Contralateral axillary metastasis (CAM) is rather rare in primary breast cancer. In this case, we present a 46-year-old female patient who underwent left breast-conserving surgery (BCS) and left axillary lymph node dissection (ALND). Two years later, an enlarged lymph node was found in her right axilla. Magnetic resonance imaging (MRI) of the breast displayed a left breast mass with multiple internal mammary lymph nodes and abnormal lymph nodes in the right axillary region. However, no abnormalities were found in the right breast. The left breast mass was diagnosed as invasive carcinoma by core needle biopsy. During the operation, we suggested that the contralateral lymph nodes were metastatic from the second primary breast cancer by preoperative 99mTc injection around the left breast. The patient underwent left mastectomy and right axillary lymph node dissection. The postoperative pathology was diagnosed as metachronous secondary primary left breast cancer, in which the initial presentation was lymph node metastasis to the contralateral axilla of the left breast. Therefore, we propose that CAM may be more common in second primary or recurrent breast cancer. It should be treated as locoregional extension. Preoperative lymph node markers are important to identify whether contralateral axillary lymph node metastasis occurs from a second primary breast cancer.


Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice.
To examine the effects of cholestatic jaundice on gut barrier function. Gut barrier failure occurs in animal models of jaundice. In humans, the presence of endotoxemia indirectly implicates failure of this host defense, but this has not previously been investigated in jaundiced patients. Twenty-seven patients with extrahepatic obstructive jaundice and 27 nonicteric subjects were studied. Intestinal permeability was measured using the lactulose-mannitol test. Small intestinal morphology and the presence of mucosal immunologic activation were examined in endoscopic biopsies of the second part of the duodenum. Systemic antiendotoxin core IgG antibodies and serum interleukin-6 and C-reactive protein were also quantified. Intestinal permeability was remeasured in 9 patients 5 weeks after internal biliary drainage. The median lactulose-mannitol ratio was significantly increased in the jaundiced patients. This was accompanied by upregulation of HLA-DR expression on enterocytes and gut-associated lymphoid tissue, suggesting immune activation. A significant increase in the acute phase response and circulating antiendotoxin core antibodies was also observed in the jaundiced patients. After internal biliary drainage, intestinal permeability returned toward normal levels. A reversible impairment in gut barrier function occurs in patients with cholestatic jaundice. Increased intestinal permeability is associated with local immune cell and enterocyte activation. In view of the role of gut defenses in the modern paradigm of sepsis, these data may directly identify an important underlying mechanism contributing to the high risk of sepsis in jaundiced patients.


Organizational impact on psychosocial working conditions.
Using a multilevel approach, this study explores how job demands and control are dependent on the organizational context in which work is performed. The data set consisted of 3,485 employees at 51 establishments divided into 141 sub-units and belonging to 10 parent organizations. Data were collected by means of a survey answered by the employees and structured interviews conducted with operative managers at participating establishments. The results showed that a significant proportion of the variance in job demands and control was attributed to the organization, and that the three organizational levels varied in terms of their impact on the two psychosocial dimensions. More specifically, job demands were mostly affected by the establishment level, while the sub-unit level seemed to be the most important for job control. It is concluded that in studies of working conditions, the organizational context should be considered.


Role of fever in ventriculoperitoneal shunt placement after aneurysmal subarachnoid hemorrhage.
Central fever is common after aneurysmal subarachnoid hemorrhage (aSAH) and may delay ventriculoperitoneal shunt (VPS) placement. We hypothesize that drain-dependent aSAH patients with central fever or persistent fever after treatment of an identifiable cause are not at an increased risk of infectious VPS failure. Patient demographics, radiographic characteristics, temperature, incidence of infection, and shunt failure were prospectively recorded in a consecutive cohort of aSAH patients. Central fever was defined as temperature higher than 38.3°C with no identifiable cause. Of 580 patients, 61 (11%) were drain dependent. Central fever developed in 18, 35 had fever of known etiology, and 8 remained afebrile. There was no shunt failure at discharge, and 2 failures (3.2%) at follow-up were attributed to infection. One patient with central fever (6%), none with fever of identifiable etiology, and 1 (13%) with no fever had infectious shunt failures at a median follow-up of 10.2 ± 3.6 months (P > .05). Nine patients with central fever (50%) and 6 (17%) who were treated for fever of known etiologies had persistent fever at shunt placement. Patients who were febrile on the day of surgery had similar infectious shunt failure rates at discharge compared with those who were afebrile (0% vs 0%; P = 1.0). Similarly, febrile and afebrile patients at VPS insertion had comparable rates of infectious shunt failure at follow-up (7% vs 2%; P = .43). aSAH patients with central fever or persistent fever after treatment of fever of identifiable etiology are not at an increased risk of infectious VPS failure.


Purification of human c-erb A beta protein.
Human thyroid hormone receptor (c-erb A protein) produced by Escherichia coli expression vector plasmid was purified sequentially using polyethylenimine precipitation of DNA, hydroxylapatite column chromatography, ammonium sulphate precipitation, Sephacryl S-300 gel filtration and mono Q-Sepharose column chromatography. These column procedures resulted in 41.3-fold purification of 3,5,3'-tri-iodo-L-thyronine (T3) binding activity over the initial E. coli extract. Purified protein as well as crude preparation showed high-affinity binding to T3. The c-erb A protein enriched by column purification was further purified by electroelution after electrophoresis. Rabbit antibody against the c-erb A protein was prepared and used for the Western blotting analysis. The antibody recognized c-erb A protein but not the bacterial proteins in crude E. coli extract. When partially purified rat hepatic nuclear thyroid hormone receptor was analysed, a 56 kDa receptor was specifically recognized by the antibody.


Hemorrhagic complications of ventriculostomy: incidence and predictors in patients with intracerebral hemorrhage.
Ventriculostomy--the placement of an external ventricular drain (EVD)--is a common procedure performed in patients with acute neurological injury. Although generally considered a low-risk intervention, recent studies have cited higher rates of hemorrhagic complications than those previously reported. The authors sought to determine the rate of postventriculostomy hemorrhage in a cohort of patients with intracerebral hemorrhage (ICH) and to identify predictors of hemorrhagic complications of EVD placement. Patients with ICH who underwent EVD placement and had both pre- and postprocedural imaging available for analysis were included in this study. Relevant data were prospectively collected for each patient who satisfied inclusion criteria. Variables with a p < 0.20 on univariate analyses were included in a stepwise logistic regression model to identify predictors of postventriculostomy hemorrhage. Sixty-nine patients were eligible for this analysis. Postventriculostomy hemorrhage occurred in 31.9% of patients. Among all patients with intraparenchymal hemorrhage, the mean hemorrhage volume was 0.66 ± 1.06 cm(3). Stratified according to ventricular catheter diameter, patients treated with smaller-diameter catheters had a significantly greater mean hemorrhage volume than patients treated with larger-diameter catheters (0.84 ± 1.2 cm(3) vs 0.14 ± 0.12 cm(3), p = 0.049). Postventriculostomy hemorrhage was clinically significant in only 1 patient (1.4%). Overall, postventriculostomy hemorrhage was not associated with functional outcome or mortality at either discharge or 90 days. In the multivariate model, an age > 75 years was the only independent predictor of EVD-associated hemorrhage. Advanced age is predictive of EVD-related hemorrhage in patients with ICH. While postventriculostomy hemorrhage is common, it appears to be of minor clinical significance in the majority of patients.


Performance of the Cobas AmpliPrep/Cobas TaqMan real-time PCR assay for hepatitis B virus DNA quantification.
Hepatitis B virus (HBV) DNA quantification is used to establish the prognosis of chronic HBV-related liver disease, to identify those patients who need to be treated, and to monitor the virologic response and resistance to antiviral therapies. Real-time PCR-based assays are gradually replacing other technologies for routine quantification of HBV DNA in clinical practice. The goal of this study was to evaluate the intrinsic characteristics and clinical performance of the real-time PCR Cobas AmpliPrep/Cobas TaqMan (CAP/CTM) platform for HBV DNA quantification. Specificity was satisfactory (95% confidence interval, 98.1 to 100%). Intra-assay coefficients of variation ranged from 0.22% to 2.68%, and interassay coefficients of variation ranged from 1.31% to 4.13%. Quantification was linear over the full dynamic range of quantification of the assay (1.7 to 8.0 log(10) IU/ml) and was not affected by dilution. The assay was accurate regardless of the HBV genotype. Samples containing HBV DNA levels above 4.5 log(10) IU/ml were slightly underestimated relative to another accurate assay based on branched-DNA technology, but this is unlikely to have noteworthy clinical implications. Thus, the CAP/CTM HBV DNA assay is sensitive, specific, and reproducible, and it accurately quantifies HBV DNA levels in patients chronically infected by HBV genotypes A to F. Samples with HBV DNA concentrations above the upper limit of quantification need to be diluted and then retested. Broad use of fully automated real-time PCR assays should improve the management of patients with chronic HBV infection.


The relevance of context in understanding health literacy skills: Findings from a qualitative study.
Conceptualizing health literacy as a relational concept, which involves how individuals interact with complex health and social systems, requires a greater understanding of the context of people's health experiences. To describe individuals' experiences of accessing, understanding, appraising and applying health information; explore the barriers and facilitators to using these skills; and to describe the experience of information exchange in health consultations. A longitudinal qualitative methodology with thematic analysis of interviews was used. Health literacy levels were assessed using the HLS-EU-47-Item Questionnaire. Findings are presented from the first round of data collection. Twenty-six participants purposefully selected from a CVD risk reduction programme at three separate time points. Four key themes identified: using health literacy capacities for managing health; psychological and structural factors that impact on these capacities; and the relationship quality with the health-care provider (HCP). Although limited health literacy was prevalent across the sample (65%), all individuals were very proactive in attempting to utilize health literacy skills. Findings emphasize the importance of contextual factors such as the quality of communication with the health-care provider, perceptions of control, attitudes to family medical history, navigating structural barriers and being supported in managing treatment and medication side-effects. Findings are relevant for health-care providers in order to enhance the patient-provider relationship and to ensure optimum health outcomes for all individuals regardless of health literacy levels.


Influence of overweight on ICU mortality: a prospective study.
Overweight patients seem to have a poorer outcome and a higher risk of complications during their stay in the ICU. We conducted a prospective study in order to examine the relationship between body mass index (BMI) and mortality among these patients. Prospective clinical study. A 24-bed medical ICU in a university-affiliated hospital. All patients hospitalized in the ICU over a 1-year period were included except those dying or being discharged from the hospital within 24 h of admission. Overweight patients were defined as those having a BMI > 75th percentile of this selected ICU population. Other data collected were demographic and ICU-related data. The Mann-Whitney test was used to compare numeric data between groups (ie, obese and nonobese populations). Variables that were significantly associated with ICU mortality by univariate analysis were entered into a multiple logistic regression model, allowing the determination of independent predictors. Eight hundred thirteen patients were included in the study. The limit of the upper quartile of the BMI was 27. This value was used to separate obese (n = 215) and nonobese (n = 598) groups. Significant differences between obese and nonobese patients were observed in age, length of stay in the ICU, simplified acute physiology score (SAPS) II, and ICU mortality. The observed mortality of obese patients was significantly higher than that predicted by SAPS II (32% vs 18%, respectively; p = 0.001). No difference was observed in frequency of nosocomial infection or duration of mechanical ventilation for mortality in ICU patients. Using a multivariate analysis, the predictive factors of mortality were SAPS II (p < 0.0001) and BMI > 27 (p < 0.01). This is the first prospective study showing high BMI value as an independent prognostic factor of mortality for ICU patients. The prognostic scoring systems currently in use, which were designed to predict the mortality of ICU patients, do not include BMI or do not consider obesity. These may underestimate, therefore, the risk for the specific population of obese patients.


Stereospecificity of nucleases towards phosphorothioate-substituted RNA: stereochemistry of transcription by T7 RNA polymerase.
Transcription by T7 RNA polymerase has been studied using a chiral ATP analogue. The Sp diastereoisomer of adenosine 5'-O-(1-thiotriphosphate) (ATP alpha S) was incorporated into RNA with an apparent KM of approximately 15 microM, similar to that for ATP; the Rp diastereoisomer was neither a substrate nor a competitive inhibitor. The configuration of the phosphodiester link in the RNA produced was analyzed with stereospecific nucleases. The rate of nuclease digestion was compared with the rate of digestion of phosphorothioate-substituted RNA of known stereochemistry synthesized by E. coli RNA polymerase. Surprisingly, the nucleases exhibited reduced discrimination compared with their activity on dinucleotides. The results show that phosphorothioate-substituted RNA transcribed by T7 RNA polymerase has the same configuration as that transcribed by E. coli RNA polymerase, ie. Rp. Thus, the reaction proceeds with inversion of configuration at phosphorus.


Transpulmonary Hypothermia with Cooled Oxygen Inhalation Shows Promising Results as a Novel Hypothermia Technique.
Therapeutic hypothermia was showed to improve neurologic outcome but current therapeutic hypothermia techniques have limitations. Novel techniques such as transpulmonary hypothermia with cooled oxygen inhalation may be beneficial. To evaluate the performance of transthoracic hypothermia with cooled medical oxygen inhalation as a therapeutic hypothermia method. Animal experimentation. A total of 36 adult male Wistar-Hannover rats were used in this research. Rats were randomised into four groups: group 1, Cooled oxygen group; group 2, IV cold fluid group; group 3, Surface cooling group; group 4, control group. No hypothermia method was applied in the control group. Hypothermia techniques were administered in the other three groups until the targeted core temperature was maintained. The target temperature was continued for one hour at 32-34 °C. After that, rats were heated up with hot blankets. Once the rectal temperature reached 38 °C, rats were euthanised. The main outcomes were the rate of temperature decrease (°C per minute) (S) and the time required to reach the target body temperature (T). All rats survived the study protocol. When compared to the control group, T and S values were better in the cooled medical oxygen inhalation group (p<0.001). The IV cold fluid group had lower S values and higher T values compared to the cooled oxygen group (p<0.001, and p=0.003, respectively). There was no meaningful pathology in the histological samples in any group. As an easy-to-use and inexpensive method, cooled oxygen inhalation may be a beneficial hypothermia technique.


The role of endotoxin in the pathogenesis of coliform mastitis in sows.
Sows were made tolerant to Escherichia coli endotoxin by daily intravenous (IV) injection of the pyrogen. A refractory state was induced, characterised by a markedly decreased fever. In contrast, intramammary (IMM) infusion of only a quarter of the endotoxin dose to which the animals were made tolerant by IV injection produced a markedly increased fever. This finding suggests that inflammatory endogenous mediators were released in the mammary glands and that their subsequent absorption into the blood circulation, and not the absorption of endotoxin caused fever.


Deep neural network-assisted high-accuracy microwave instantaneous frequency measurement with a photonic scanning receiver.
A microwave instantaneous frequency measurement system with a photonic scanning receiver is proposed in which deep neural network (DNN)-assisted frequency estimation is used to deal with the system defects and improve the accuracy. The system performs frequency-to-time mapping by optical-domain frequency scanning and electrical-domain intermediate frequency envelop detection. Thanks to the optical frequency multiplication, the system can measure high frequency signals in a large spectral range. The DNN establishes an accurate mapping between the digital samples and real frequencies, based on which high-accuracy measurement is achieved. The measurement of signals from 43 to 52 GHz is experimentally demonstrated. Compared with the direct measurements, the DNN-assisted method achieves obviously reduced average errors of about 3.2 MHz.


Laryngotracheal separation in pediatric patients: 13-year experience in a reference service.
To evaluate clinical stability of neurologically impaired children and adolescents with recurrent pneumonia submitted to laryngotracheal separation. Between October 2002 and June 2015, 92 neurologically impaired children from a reference service, with median age of 68.5 months were submitted to laryngotracheal separation. Data were evaluated and statistical analysis was made by Student's t test and Pearson's χ2 test (significance level adopted of 95%). Fifty-three children were male (57.6%). Forty-six children required admission to intensive care, and 42.4% needed mechanical ventilation. We observed that 90.2% of patients were exclusively fed by gastrostomy and 72.4% of the gastrostomies were performed before the tracheal surgery. Thirteen (14.1%) children had postoperative complications as follows: fistulae (5.4%), bleeding (4.3%), granuloma (2.2%) and stenosis (3.2%). A total of 24 patients had pneumonia in the postoperative period (26.1%), but there was a significant drop in occurrence of this condition after surgery (100% versus 26.1%; p<0.001). Twenty-three patients (25%) died. Postoperative complications were similar when comparing patients who died and those that presented good outcome (16.7% versus 13.2%; p=0.73). When well-indicated, the laryngotracheal separation reduces the incidence of postoperative pulmonary infections, thus improving quality of life and reducing admissions to hospital. Laryngotracheal separation should be indicated as a primary procedure in patients with cerebral palsy and recurrent aspiration pneumonia.


Some effects of motor-car driving on the normal and abnormal heart.
Electrocardiograms were recorded in experienced motor-car drivers accustomed to busy city traffic while driving their own cars along familiar routes. The majority with normal hearts or a history of coronary heart disease increased their heart rates; brief periods when the rate exceeded 140/min. were recorded in both groups. ST changes not caused by tachycardia developed in 3 out of 32 normal drivers. Of 24 drivers with coronary heart disease 13 increased their ST and T abnormalities, the changes being gross in six. A further five developed multiple ventricular ectopic beats. Two coronary drivers experienced anginal pain and two left ventricular failure. Healthy motor-racing drivers increased their heart rates to 180/min. in the few minutes before the start of a race and to above 200/min. while racing.Little or no change in the plasma catecholamine levels was noted in three coronary subjects immediately after a city drive compared with resting levels. All the racing drivers showed a considerable increase in noradrenaline, and in one instance adrenaline, immediately after racing.Persons in whom angina is easily provoked when driving or who are in borderline left ventricular failure should be advised not to drive.


Hellenic consensus on Helicobacter pylori infection.
The Hellenic Society of Gastroenterology recently organized the "Hellenic consensus on Helicobacter pylori (H. pylori) infection". The aim of this publication is to report the guidelines in order to aid the national gastroenterology community in the management of H. pylori infection. Forty-one delegates from all Greek regions, including gastroenterologists, pathologists, clinical microbiologists, epidemiologists and basic scientists, were invited to this meeting. The participants were allocated to 1 of the 4 main topics of the meeting: i.e., H. pylori diagnosis and association with diseases; H. pylori and gastric cancer; H. pylori and extragastric associated disorders; and H. pylori treatment. The results of each subgroup were submitted to a final consensus vote that included all participants. Relevant data based on international and Greek publications were presented, and the quality of evidence, strength of recommendation, and level of consensus were graded. The cutoff level of 70% was considered as acceptance for the final statement. It is hoped that the recommendations and conclusions of this report will guide Greek doctors in their daily practice concerning the management of H. pylori infection.


Are we choosing the right flagships? The bird species and traits Australians find most attractive.
Understanding what people like about birds can help target advocacy for bird conservation. However, testing preferences for characteristics of birds is methodologically challenging, with bias difficult to avoid. In this paper we test whether preferred characteristics of birds in general are shared by the individual bird species the same people nominate as being those they consider most attractive. We then compare these results with the birds which appear most frequently in the imagery of conservation advocates. Based on a choice model completed by 638 general public respondents from around Australia, we found a preference for small colourful birds with a melodious call. However, when the same people were asked which five birds they found most attractive, 48% named no more than three, mostly large well-known species. Images displayed by a leading Australian bird conservation organisation also favoured large colourful species. The choice model results suggest conservation advocates can promote a much wider range of bird types as flagships, particularly smaller species that might otherwise be neglected.


CHA2DS2-VASc Score for Identifying Truly Low-Risk Atrial Fibrillation for Stroke: A Korean Nationwide Cohort Study.
As the threshold of stroke risk for initiating oral anticoagulants is lowered after the introduction of the nonvitamin K antagonist oral anticoagulants, the focus of stroke prevention in patients with nonvalvular atrial fibrillation has shifted away from predicting high-risk patients toward initially identifying patients with a truly low risk of ischemic stroke, who do not need antithrombotic therapy. We tested the predictive ability of the congestive heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack (doubled; CHADS2), congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65 to 74, female (CHA2DS2-VASc), and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk stratification schemes in oral anticoagulants naive patients with atrial fibrillation in a Korean nationwide sample cohort. From January 2002 to December 2008, a total of 5855 oral anticoagulant naive patients with nonvalvular atrial fibrillation aged ≥20 years were enrolled from Korea National Health Insurance Service-Sample Cohort database and were followed-up until December 2013. At baseline, the proportions categorized as low risk using CHADS2, CHA2DS2-VASc, and ATRIA risk stratification schemes were 1049 (17.9%), 860 (14.7%), and 3280 (56.0%), respectively. During follow-up, the low-risk category using CHADS2, CHA2DS2-VASc, and ATRIA scores was retained in 811 (13.9%), 667 (11.4%), and 2729 (46.6%) patients, respectively. Rates of ischemic stroke (100 person-years) in the low risk categories of CHADS2, CHA2DS2-VASc, and ATRIA scores were 0.42, 0.26, and 1.43, respectively. CHA2DS2-VASc had the best sensitivity (98.8% versus 85.7% in CHADS2 and 74.8% in ATRIA) and negative predictive value (98.8% versus 95.3% for CHADS2 and 93.7% for ATRIA) for the prediction of stroke incidence and was best for the prediction of the absence of ischemic stroke during 5 years of follow-up (odds ratio, 16.4 [95% confidence interval, 8.8-30.8]). The CHA2DS2-VASc score shows good performance in defining truly low-risk Asian patients with atrial fibrillation for stroke compared with CHADS2 and ATRIA scores.


Audiological findings in aphasic patients after stroke.
To outline the audiological findings of aphasic patients after cerebrovascular accidents. This is a cross-sectional study performed between March 2011 and August 2012 in the Speech, Language, and Hearing Pathology Department of the Universidade Federal de São Paulo. A total of 43 aphasic subjects (27 men) were referred for audiological evaluation after stroke, with mean age of 54.48 years. Basic audiological evaluation tests were performed, including pure tone audiometry, speech audiometry (speech recognition threshold and word recognition score), immittance measures (tympanometry and contralateral acoustic reflex), and transient otoacoustic emissions. Sensorineural hearing loss was prevalent (78.6%). Speech recognition threshold and word recognition score were not obtained in some patients because they were unable to perform the task. Hearing loss was a common finding in this population. Comprehension and/or oral emission disruptions in aphasic patients after stroke compromised conventional speech audiometry, resulting in the need for changes in the evaluation procedures for these patients.


The Role of Excitability and Network Structure in the Emergence of Focal and Generalized Seizures.
Epileptic seizures are generally classified as either focal or generalized. It had been traditionally assumed that focal seizures imply localized brain abnormalities, whereas generalized seizures involve widespread brain pathologies. However, recent evidence suggests that large-scale brain networks are involved in the generation of focal seizures, and generalized seizures can originate in localized brain regions. Herein we study how network structure and tissue heterogeneities underpin the emergence of focal and widespread seizure dynamics. Mathematical modeling of seizure emergence in brain networks enables the clarification of the characteristics responsible for focal and generalized seizures. We consider neural mass network dynamics of seizure generation in exemplar synthetic networks and we measure the variance in ictogenicity across the network. Ictogenicity is defined as the involvement of network nodes in seizure activity, and its variance is used to quantify whether seizure patterns are focal or widespread across the network. We address both the influence of network structure and different excitability distributions across the network on the ictogenic variance. We find that this variance depends on both network structure and excitability distribution. High variance, i.e., localized seizure activity, is observed in networks highly heterogeneous with regard to the distribution of connections or excitabilities. However, networks that are both heterogeneous in their structure and excitability can underlie the emergence of generalized seizures, depending on the interplay between structure and excitability. Thus, our results imply that the emergence of focal and generalized seizures is underpinned by an interplay between network structure and excitability distribution.


Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-tolerant mice.
Repetitive hypoxic preconditioning creates long-lasting, endogenous protection in a mouse model of stroke, characterized by reductions in leukocyte-endothelial adherence, inflammation, and infarct volumes. The constitutively expressed chemokine CXCL12 can be upregulated by hypoxia and limits leukocyte entry into brain parenchyma during central nervous system inflammatory autoimmune disease. We therefore hypothesized that the sustained tolerance to stroke induced by repetitive hypoxic preconditioning is mediated, in part, by long-term CXCL12 upregulation at the blood-brain barrier (BBB). In male Swiss Webster mice, repetitive hypoxic preconditioning elevated cortical CXCL12 protein levels, and the number of cortical CXCL12+ microvessels, for at least two weeks after the last hypoxic exposure. Repetitive hypoxic preconditioning-treated mice maintained more CXCL12-positive vessels than untreated controls following transient focal stroke, despite cortical decreases in CXCL12 mRNA and protein. Continuous administration of the CXCL12 receptor (CXCR4) antagonist AMD3100 for two weeks following repetitive hypoxic preconditioning countered the increase in CXCL12-positive microvessels, both prior to and following stroke. AMD3100 blocked the protective post-stroke reductions in leukocyte diapedesis, including macrophages and NK cells, and blocked the protective effect of repetitive hypoxic preconditioning on lesion volume, but had no effect on blood-brain barrier dysfunction. These data suggest that CXCL12 upregulation prior to stroke onset, and its actions following stroke, contribute to the endogenous, anti-inflammatory phenotype induced by repetitive hypoxic preconditioning.


Thyroparathyroidectomy increases the activity of catalase in the adrenal gland of the rat. A structural and functional study.
At four weeks after thyroparathyroidectomy the activity of catalase in adrenal homogenates was significantly greater (2.95 +/- 0.06 mumoles 0(2)/min/mg protein) than that of controls (2.17 +/- 0.09 mumoles 0(2)/min/mg protein). Increased activity of catalase is related directly to more numerous peroxisomes in cortical cells in the zona fasciculata-zona reticularis of thyroparathyroidectomized rats. The absolute and relative volumes of adrenal gland and zona fasciculata were reduced significantly which is directly correlated with increased peroxisomal activity. A hormonally mediated mechanism reflecting alteration in ACTH, growth hormones and thyroid hormones may mediate adrenocortical atrophy and in turn increase in activity of catalase.


Antibody producing capacity to the bacteriophage phi X174 in rheumatoid arthritis.
A study of antibody production in response to a primary immunogen, the bacteriophage phi X174, was performed in 27 patients with rheumatoid arthritis and 15 controls. All patients produced a primary (IgM) response to initial immunisation. The frequency distribution of peak antibody titres after secondary immunisation showed a marked difference between the patients and controls, with 10 patients having peak titres below 5000. The IgG component of the antibody response expressed as a percentage of total phage antibody on the 10th day after secondary immunisation was less in the patients than in the control group. There was no correlation between antibody titres and indices of disease activity, rheumatoid factor titres, or the presence of DRw4, DRw3, and DRw2. After secondary immunisation the patients with rheumatoid arthritis were treated with D-penicillamine, azathioprine, levamisole, or maintained on a non-steroidal anti-inflammatory drug. Assessment of response to tertiary immunisation again showed an impairment of antibody production in the rheumatoid group receiving non-steroidal anti-inflammatory drugs compared with the controls. None of the drugs, D-penicillamine, azathioprine, or levamisole, produced further suppression or augmentation of antibody production in response to the immunogen.


Hospital Length of Stay and Readmission Rate for Neurosurgical Patients.
Hospital readmission rate has become a major indicator of quality of care, with penalties given to hospitals with high rates of readmission. At the same time, insurers are increasing pressure for greater efficiency and reduced costs, including decreasing hospital lengths of stay (LOS). To analyze the authors' service to determine if there is a relationship between LOS and readmission rates. Records of patients admitted to the authors' institution from October 2007 through June 2014 were analyzed for several data points, including initial LOS, readmission occurrence, admitting and secondary diagnoses, and discharge disposition. Out of 9409 patient encounters, there were 925 readmissions. Average LOS was 6 d. Univariate analysis indicated a higher readmission rate with more diagnoses upon admission (P < .001) and an association between insurance type and readmission (P < .001), as well as decreasing average yearly LOS (P = .0045). Multivariate analysis indicated statistically significant associations between longer LOS (P = .03) and government insurance (P < .01). A decreasing LOS over time has been associated with an increasing readmission rate at the population level. However, at the individual level, a prolonged LOS was associated with a higher risk of readmission. This was attributed to patient comorbidities. However, this increasing readmission rate may represent many factors including patients' overall health status. Thus, the rate of readmission may represent a burden of illness rather than a valid metric for quality of care.


[Overweight and obesity repercussion in the postoperative of myocardial revascularization surgery].
This is a descriptive, retrospective study with cross-sectional quantitative approach, which aimed to relate the body mass index with events in the postoperative period of the myocardial revascularization surgery with use of extracorporeal circulation. The data collection period was between April and June/2012. Patients were divided according to the body mass index and classified as without excess of weight, overweight or obese. The data analysis was based on the descriptive statistics. The patients without excess of weight had more complications, especially those related to the lungs. Among overweight and obese individuals, the cardiovascular complications stood out. The obese subjects had the worse prognostic. Obesity and overweight did not have statistically significant association with a higher frequency of postoperative complications, in spite of the occurrence of cardiovascular complications in this group. The patients without excess of weight had higher risks of developing neurological events.


Large depolarization induces long openings of voltage-dependent calcium channels in adrenal chromaffin cells.
Single Ca2+-channel currents in bovine adrenal chromaffin cells were studied with the patch-clamp technique using Ba2+ as the charge carrier. Depolarizing pulses to voltages less than +10 mV from holding voltage of -60 mV elicited short openings with a mean life time of less than 1 msec. Depolarization to more positive voltages elicited longer openings with a mean life time of about 3 msec in addition to the short openings similar to those observed at less positive voltages. Following large depolarizing prepulses, 2 types of "tail" openings, one with a mean duration of less than 1 msec and the other with a mean duration of 4 msec, were observed. In the presence of a dihydropyridine BAY K 8644, openings with a mean duration of more than 12 msec were present. Depolarization-induced long openings and BAY K 8644-produced long openings differed in the first latency and open-time properties. The results could be explained in terms of multiple open states of one type of Ca2+ channel. A kinetic model with at least 2 open states is required to explain activation of Ca2+ channels in chromaffin cells.


Assessing Suicide Reporting in Top Newspaper Social Media Accounts in China: Content Analysis Study.
Previous studies have shown that suicide reporting in mainstream media has a significant impact on suicidal behaviors (eg, irresponsible suicide reporting can trigger imitative suicide). Traditional mainstream media are increasingly using social media platforms to disseminate information on public-related topics, including health. However, there is little empirical research on how mainstream media portrays suicide on social media platforms and the quality of their coverage. This study aims to explore the characteristics and quality of suicide reporting by mainstream publishers via social media in China. Via the application programming interface of the social media accounts of the top 10 Chinese mainstream publishers (eg, People's Daily and Beijing News), we obtained 2366 social media posts reporting suicide. This study conducted content analysis to demonstrate the characteristics and quality of the suicide reporting. According to the World Health Organization (WHO) guidelines, we assessed the quality of suicide reporting by indicators of harmful information and helpful information. Chinese mainstream publishers most frequently reported on suicides stated to be associated with conflict on their social media (eg, 24.47% [446/1823] of family conflicts and 16.18% [295/1823] of emotional frustration). Compared with the suicides of youth (730/1446, 50.48%) and urban populations (1454/1588, 91.56%), social media underreported suicides in older adults (118/1446, 8.16%) and rural residents (134/1588, 8.44%). Harmful reporting practices were common (eg, 54.61% [1292/2366] of the reports contained suicide-related words in the headline and 49.54% [1172/2366] disclosed images of people who died by suicide). Helpful reporting practices were very limited (eg, 0.08% [2/2366] of reports provided direct information about support programs). The suicide reporting of mainstream publishers on social media in China broadly had low adherence to the WHO guidelines. Considering the tremendous information dissemination power of social media platforms, we suggest developing national suicide reporting guidelines that apply to social media. By effectively playing their separate roles, we believe that social media practitioners, health institutions, social organizations, and the general public can endeavor to promote responsible suicide reporting in the Chinese social media environment.


Endocytosis of a small dermatan sulphate proteoglycan. Identification of binding proteins.
Endosomal preparations from human osteosarcoma cells and from fibroblasts contain 51,000- and 26,000-Mr proteins which bind a small dermatan sulphate proteoglycan after SDS/polyacrylamide-gel electrophoresis and Western blotting. Binding can be inhibited by unlabelled proteoglycan core protein. The proteins co-precipitate with a proteoglycan core protein-antibody complex. Scatchard analysis of immobilized endosomal proteins yielded a KD of about 37 nM for the proteoglycan. In intact cells proteins of the same size can be found. They are sensitive to trypsinization. A 51,000-Mr protein is the predominant membrane protein with strong binding to immobilized dermatan sulphate proteoglycan. There are additional proteoglycan-binding proteins with Mr values of around 30,000 and 14,000 which are insensitive to trypsin treatment. In contrast with the 51,000- and 26,000-Mr proteins, they resist deoxycholate/Triton X-100 extraction several days after subcultivation.


Pancreatic oncofetal antigen in the detection of experimental cancer of the pancreas.
A hamster serum protein which reacted with anti-human pancreatic oncofetal antigen (POA) was identified in sera from hamsters with varying types of pancreatic pathology. Hamsters were treated with N-nitrobis-(2-hydroxypropyl)-amine, and histological findings in the pancreas were correlated with hamster POA. The cross reactivity of anti-human POA with hamster POA was poor. As a result, the sensitivity of this assay was too low to permit its use in serologically discriminating carcinogen-induced pancreatic cancer from other pancreatic pathologies. A specific antiserum and assay system to hamster POA may overcome this problem.


Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
We searched the literature on the epidemiology, diagnosis, prognosis, treatment and costs of mild traumatic brain injury. Of 428 studies related to prognosis after mild traumatic brain injury, 120 (28%) were accepted after critical review. These comprise our best-evidence synthesis on prognosis after mild traumatic brain injury. There was consistent and methodologically sound evidence that children's prognosis after mild traumatic brain injury is good, with quick resolution of symptoms and little evidence of residual cognitive, behavioural or academic deficits. For adults, cognitive deficits and symptoms are common in the acute stage, and the majority of studies report recovery for most within 3-12 months. Where symptoms persist, compensation/litigation is a factor, but there is little consistent evidence for other predictors. The literature on this area is of varying quality and causal inferences are often mistakenly drawn from cross-sectional studies.


A review of penile cancer.
Cancer of the penis is a rare tumour in Europe and mainly affects the elderly patient population. The aim of this paper was to analyse and study the characteristics of this tumour, in our patient population. A retrospective study was conducted on penile tumours diagnosed and treated in the Urology Department of the Hospital Universitario La Paz, Madrid, in the last ten years. A total of 34 patients were diagnosed and treated. The mean age at presentation was 71.27 years. The mean time between symptoms and the first consultation was 12.54 months with a median of 6 months. The most common form of presentation was balanoposthitis (32%) and the most common site in our series was the glans. Partial penectomy was performed in 22 cases, total amputation in 8, and local excision in 3. Carcinoma of the penis is a pathology which mostly affects elderly patients; in our series, the highest incidence was observed in patients in the group aged 75-84 years. The most common histological type was epidermoid carcinoma in its various forms of presentation. We recorded a mortality of 23%. Penile carcinoma is a rare pathology which affects elderly persons and is diagnosed late.


Genome sequencing in myelodysplastic syndromes: can molecular mutations predict benefit from hypomethylating agent therapy?
Evaluation of: Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014 Oct 23;124(17):2705-12. Patients with myelodysplastic syndromes (MDS) have clinically variable courses even within the same prognostic subgroups. Although hypomethylating agents (HMAs) have been shown to improve outcomes in patients with high-risk MDS, many patients do not derive benefit. There is an urgent clinical need to identify patients with low probability of benefiting from HMAs but no reliable clinical predictors or biomarkers have been discovered to date. Although some recurrent molecular mutations in MDS carry independent prognostic value, their ability to predict benefit from HMAs is not clear. Here, we discuss an important article in which sequencing from samples of 213 patients identified recurrent mutations associated with response to HMAs. Although an important step in the right direction, the clinical implications of these findings are far from optimal and identification of biomarkers that can reliably predict benefit from HMAs and other therapies in patients with MDS remains a top clinical and a research priority.


Neurocutaneous melanosis.
Neurocutaneous melanosis (NCM) is a rare phakomatosis characterized by a focal or diffuse proliferation of melanin-producing cells in both the skin and the leptomeninges. This syndrome is believed to result from an error in the morphogenesis of embryonal neuroectoderm. Two-thirds of patients with NCM have giant congenital melanocytic nevi, and the remaining third have numerous lesions but no giant lesions. Most patients present neurological manifestations early in life, which can be secondary to intracranial hemorrhages, to impairment of cerebrospinal fluid circulation, and to malignant transformation of the melanocytes. The prognosis of patients with symptomatic neurocutaneous melanosis is extremely poor, even in the absence of malignancy. Chemotherapy has been ineffective in the few patients in whom it has been tried.


Individual and work-related risk factors for musculoskeletal pain: a cross-sectional study among Estonian computer users.
Occupational use of computers has increased rapidly over recent decades, and has been linked with various musculoskeletal disorders, which are now the most commonly diagnosed occupational diseases in Estonia. The aim of this study was to assess the prevalence of musculoskeletal pain (MSP) by anatomical region during the past 12 months and to investigate its association with personal characteristics and work-related risk factors among Estonian office workers using computers. In a cross-sectional survey, the questionnaires were sent to the 415 computer users. Data were collected by self-administered questionnaire from 202 computer users at two universities in Estonia. The questionnaire asked about MSP at different anatomical sites, and potential individual and work related risk factors. Associations with risk factors were assessed by logistic regression. Most respondents (77%) reported MSP in at least one anatomical region during the past 12 months. Most prevalent was pain in the neck (51%), followed by low back pain (42%), wrist/hand pain (35%) and shoulder pain (30%). Older age, right-handedness, not currently smoking, emotional exhaustion, belief that musculoskeletal problems are commonly caused by work, and low job security were the statistically significant risk factors for MSP in different anatomical sites. A high prevalence of MSP in the neck, low back, wrist/arm and shoulder was observed among Estonian computer users. Psychosocial risk factors were broadly consistent with those reported from elsewhere. While computer users should be aware of ergonomic techniques that can make their work easier and more comfortable, presenting computer use as a serious health hazard may modify health beliefs in a way that is unhelpful.


Use of genetically modified bacteria for drug delivery in humans: Revisiting the safety aspect.
The use of live, genetically modified bacteria as delivery vehicles for biologics is of considerable interest scientifically and has attracted significant commercial investment. We have pioneered the use of the commensal gut bacterium Bacteroides ovatus for the oral delivery of therapeutics to the gastrointestinal tract. Here we report on our investigations of the biological safety of engineered B. ovatus bacteria that includes the use of thymineless death as a containment strategy and the potential for the spread of transgenes in vivo in the mammalian gastrointestinal tract. We demonstrate the ability of GM-strains of Bacteroides to survive thymine starvation and overcome it through the exchange of genetic material. We also provide evidence for horizontal gene transfer in the mammalian gastrointestinal tract resulting in transgene-carrying wild type bacteria. These findings sound a strong note of caution on the employment of live genetically modified bacteria for the delivery of biologics.


X-Bolt unforeseen placement complication: case report.
With the introduction of the World Hip Trauma Evaluation Four clinical trial, fixation of pertrochanteric neck of femur fractures is becoming a hot topic. In this trial, the novel X-Bolt expanding bolt implant is being compared with the current gold standard of a sliding hip screw. We present a previously undescribed complication when inserting the bolt into the femoral head, where the expandable wings penetrate the femoral neck due to misplacement of the bone crusher or the X-Bolt prosthesis. This unforeseen complication required the introduction of several additional corrective intraoperative steps.


In vitro and in vivo effects on neural crest stem cell differentiation by conditional activation of Runx1 short isoform and its effect on neuropathic pain behavior.
Runx1, a Runt domain transcription factor, controls the differentiation of nociceptors that express the neurotrophin receptor Ret, regulates the expression of many ion channels and receptors, and controls the lamina-specific innervation pattern of nociceptive afferents in the spinal cord. Moreover, mice lacking Runx1 exhibit specific defects in thermal and neuropathic pain. We investigated whether conditional activation of Runx1 short isoform (Runx1a), which lacks a transcription activation domain, influences differentiation of neural crest stem cells (NCSCs) in vitro and in vivo during development and whether postnatal Runx1a activation affects the sensitivity to neuropathic pain. We activated ectopic expression of Runx1a in cultured NCSCs using the Tet-ON gene regulatory system during the formation of neurospheres and analyzed the proportion of neurons and glial cells originating from NCSCs. In in vivo experiments we applied doxycycline (DOX) to pregnant mice (days 8-11), i.e. when NCSCs actively migrate, and examined the phenotype of offsprings. We also examined whether DOX-induced activation of Runx1a in adult mice affects their sensitivity to mechanical stimulation following a constriction injury of the sciatic nerve. Ectopic Runx1a expression in cultured NCSCs resulted in predominantly glial differentiation. Offsprings in which Runx1a had been activated showed retarded growth and displayed megacolon, pigment defects, and dystrophic dorsal root ganglia. In the neuropathic pain model, the threshold for mechanical sensitivity was markedly increased following activation of Runx1a. These data suggest that Runx1a has a specific role in NCSC development and that modulation of Runx1a activity may reduce mechanical hypersensitivity associated with neuropathic pain.