Protein side-chain dynamics observed by solution- and solid-state NMR: comparative analysis of methyl 2H relaxation data.
Rapid advances in solid-state MAS NMR made it possible to probe protein dynamics on a per-residue basis, similar to solution experiments. In this work we compare methyl 2H relaxation rates measured in the solid and liquid samples of alpha-spectrin SH3 domain. The solution data are treated using a model-free approach to separate the contributions from the overall molecular tumbling and fast internal motion. The latter part forms the basis for comparison with the solid-state data. Although the accuracy of solid-state measurements is limited by deuterium spin diffusion, the results suggest a significant similarity between methyl dynamics in the two samples. This is a potentially important observation, preparing the ground for combined analysis of the dynamics data by solid- and solution-state NMR.


Effects of local anesthetic or systemic analgesia on pain associated with cautery disbudding in calves: A systematic review and meta-analysis.
Disbudding is a common management procedure performed on dairy farms and, when done without pain mitigation, is viewed as a key welfare issue. Use of pain control has increased in recent years, but full adoption of anesthesia and analgesia by veterinarians or dairy producers has not been achieved. This may in part be due to the lack of a consistent recommendations of treatment protocols between studies examining pain control methods for disbudding. The objective of this systematic review was to examine the effects of these pain control practices for the most common method of disbudding, cautery, on outcomes associated with disbudding pain in calves. The outcomes were plasma cortisol concentrations, pressure sensitivity of the horn bud area, and validated pain behaviors (ear flick, head shake, head rub, foot stamp, and vocalization). Intervention studies describing cautery disbudding in calves 12 wk of age or younger were eligible, provided they compared local anesthesia, nonsteroidal anti-inflammatory drug (NSAID), or local anesthesia and NSAID to 1 or more of local anesthesia, NSAID, or no pain control. The search strategy used the Agricola, Medline (via OvidSP), and Web of Science databases, as well as the Searchable Proceedings of Animal Conferences (S-PAC), ProQuest Dissertations and Theses Database, and Open Access Theses and Dissertations. Meta-analysis was performed for all outcomes measured at similar time points with more than 2 studies. Local anesthetic was associated with reduced plasma cortisol until 2 h postdisbudding; however, a rise in cortisol was observed in the meta-analysis of studies reporting at 4 h postdisbudding. Heterogeneity was present in several of the analyses for this comparison. The addition of NSAID to local anesthetic showed reduction in plasma cortisol at 4 h, and a reduction in pressure sensitivity and pain behaviors in some analyses between 3 and 6 h postdisbudding. Heterogeneity was present in some meta-analyses, including several using pain behavior outcomes. This may reflect the variation in measurement time periods for behavioral measures between studies, as well as differences among NSAID treatments. Overall, a protective effect of local anesthetic was seen for the acute pain of cautery disbudding, and the delayed rise in cortisol was mitigated by the addition of an NSAID, which also reduced other signs of pain, including pressure sensitivity and pain behaviors. Based on these findings, we recommend use of local anesthetic and an NSAID as best practices for pain mitigation for cautery disbudding of calves 12 wk of age or less. The magnitude and duration of the effect of NSAID treatment was not possible to deduce from the literature because wide variation existed between studies. We recommend consideration of more standardized outcome measurements, especially for pain behaviors. Adherence to reporting guidelines by authors would help ensure more transparent and complete information is available to end users.


Activity of Ceftazidime-Avibactam against Clinical and Isogenic Laboratory Pseudomonas aeruginosa Isolates Expressing Combinations of Most Relevant β-Lactam Resistance Mechanisms.
The activity of ceftazidime-avibactam was compared with that of ceftazidime alone and meropenem against a collection of 190 Pseudomonas aeruginosa clinical isolates recovered from a multicenter study of bloodstream infections. The addition of avibactam increased ceftazidime susceptibility in the complete collection of strains (64.7% to 91.1%) and particularly among subsets of isolates showing AmpC hyperproduction (10.9% to 76.1%) or multidrug resistance (MDR) profiles (27% to 77.8%). The MICs of ceftazidime-avibactam, in contrast with those of ceftazidime or meropenem, remained at ≤4 μg/ml for a panel of 16 P. aeruginosa PAO1 isogenic mutants expressing multiple combinations of the most relevant β-lactam resistance mechanisms.


Text Materialities, Affordances, and the Embodied Turn in the Study of Reading.
Digital texts have for decades been a challenge for reading research, creating a range of questions about reading and a need for new theories and concepts. In this paper, we focus on materialities of texts and suggest an embodied, enacted, and extended approach to the research on digital reading. We refer to findings showing that cognitive activities in reading are grounded in bodily and social experiences, and we explore the cognitive role of the body in reading, claiming that-influenced by tacit knowledge and the task at hand-textual meaning is enacted through a mental and physical engagement with text. Further, applying the concept of affordances, we examine how digital technologies have induced new ways of physically handling and mentally interpreting text, indicating that brain, body, text, and technologies are integrated parts of an extended process of reading. The aim of the paper is to encourage empirical research on the interplay between body (including brain), text, and text materialities, a focus we argue will deepen our understand of the current transformation of reading.


Application of synchrotron radiation to ultrafast spectroscopy.
A novel application of synchrotron radiation to ultrafast optical spectroscopy is demonstrated. The application is based on the short coherence time of broadband synchrotron radiation and employs a conventional interferometer. From a detailed study of the coherence of synchrotron radiation, it is shown that the coherent interference between two synchrotron radiation beams, split from a single beam, can provide ultimate time resolution down to a few femtoseconds. Experimental results of ultrafast spectroscopy using broadband synchrotron radiation are presented; these include free-induction decay and photon echoes in the visible and ultraviolet regions.


Stabilization and reutilization of Bacillus megaterium glucose dehydrogenase by immobilization.
Glucose dehydrogenase (GDH) from Bacillus megaterium was immobilized using aminopropyl controlled-pore silica (CPS, average pore sizes of 170 and 500 A) as a support and glutaraldehyde as a bifunctional crosslinking agent. The CPS-immobilized enzyme could be reused 12 times and the best results were obtained using aminopropyl CPS-500 and bovine serum albumin as a feeder for stabilizing the protein layer on the support. DEAE-Sephadex (A-25 and A-50) was also used as a support for immobilizing GDH, with yields of around 42% for A-25 and 25-30% for A-50. The effect of pH on the immobilization procedure showed pH 6.5 to be better than pH 7.5 with respect to the recovery of enzyme activity. Both preparations of DEAE-Sephadex immobilized GDH could be reused several times and were thermostable at 40 degrees C for 7 h. The kinetic parameters as Michaelis constant and maximum rate were determined for the immobilized enzyme and compared with those for the freeform.


Prion-like p53 Amyloids in Cancer.
The global transcription factor, p53, is a master regulator of gene expression in cells. Mutations in the TP53 gene promote unregulated cell growth through the inactivation of downstream effectors of the p53 pathway. In fact, mutant p53 is highly prone to misfolding and frequently resides inside the cell as large aggregates, causing loss of physiological function of the tumor-suppressor protein. Here, we review the plausible reasons for functional loss of p53, including amyloid formation leading to unhindered cancer progression. We discuss previous as well as recent findings regarding the amyloid formation of p53 in vitro and in vivo. We elaborate on prion-like properties of p53 amyloids and their possible involvement in cancer progression. Because the p53 pathway is historically most targeted for the development of anticancer therapeutics, we have also summarized some of the recent approaches and advances in reviving the antiproliferative activities of wild-type p53. In this Perspective, we provide insight into understanding p53 as a prion-like protein and propose cancer to be recognized as an amyloid or prion-like disease.


High expression of aldo-keto reductase 1B10 is an independent predictor of favorable prognosis in patients with hepatocellular carcinoma.
Upregulation of aldo-keto reductase 1B10 (AKR1B10) through the mitogenic activator protein-1 signaling pathway might promote hepatocarcinogenesis and tumor progression. The goal of this study was to evaluate the prognostic significance of AKR1B10 protein expression in patients with hepatocellular carcinoma after surgery. A tissue microarray was used to detect the expression level of AKR1B10 protein in tumors from 255 patients with hepatocellular carcinoma who underwent curative hepatectomy. The impact of AKR1B10 expression on the survival of patients was analyzed. The median follow-up period was 119.8 months. High AKR1B10 protein expression was observed in 125 of the 255 patients with hepatocellular carcinoma (49.0%). High AKR1B10 expression was significantly associated with a lack of invasion of the major portal vein (p=0.022), a lack of intrahepatic metastasis (p=0.010), lower the American Joint Committee on Cancer T stage (p=0.016), lower the Barcelona Clinic Liver Cancer stage (p=0.006), and lower α-fetoprotein levels (p=0.020). High AKR1B10 expression was also correlated with a lack of early recurrence (p=0.022). Multivariate analyses of survival revealed that intrahepatic metastases and lower albumin levels were independent predictors of both shorter recurrence-free survival and shorter disease-specific survival. High AKR1B10 expression was an independent predictor of both longer recurrence-free survival (p=0.024) and longer disease-specific survival (p=0.046). High AKR1B10 protein expression might be useful as a marker of a favorable prognosis in patients with hepatocellular carcinoma after curative hepatectomy.


Effect of day length on luteinizing hormone beta-subunit mRNA and subsequent gonadal growth in the white-crowned sparrow, Zonotrichia leucophrys gambelii.
We have applied a cDNA probe for chicken luteinizing hormone beta-subunit to adenohypophysial preparations collected from Gambell's white-crowned sparrows. In situ hybridization showed luteinizing hormone (LH) beta-subunit mRNA distributed throughout the adenohypophysis in a manner identical to that of LH visualized by immunocytochemistry. Northern blot analysis showed a single band (0.8 kbp) identical to that from Japanese quail. Dot blot analysis was used to quantify changes in LH beta-subunit mRNA during a photoperiodically induced gonadal cycle in white-crowned sparrows. Transfer of adult males from short days (8L 16D) to long days (20L 4D) resulted in rapid testicular growth accompanied by increases in plasma levels of LH and body and liver mass. By Day 30 of photostimulation, mRNA levels in the adenohypophysis were significantly higher than those in birds on short days. In photorefractory birds, i.e., when gonads were regressed (60 days of long days), mRNA levels were significantly lower than on Day 30 of photostimulation. The increase in mRNA during photostimulation was accompanied by a highly significant increase in plasma concentrations of LH. The binding of iodinated LH to testes peaked at Day 15 of photostimulation and declined by Day 30. Curiously, peak production of testosterone and cAMP (induced by incubation with gonadotropins in vitro) were highest at Day 30. By 60 days of photostimulation, when birds were photorefractory, plasma levels of LH, binding of LH to the testes, and testosterone and cAMP production were greatly reduced. These data suggest that photoperiodically induced gonadal development and regression is mediated in part by regulation of mRNA levels for LH beta-subunit in the adenohypophysis.


Survival of nosocomial pathogenic bacteria at ambient temperature.
Staphylococcus aureus and many gram-negative rods are prevalent nosocomial pathogens. The mechanisms by which these organisms persist and spread within the hospital environment have not been clearly defined. We found that these bacteria have an extraordinary capability for survival in the environment. The viabilities of staphylococcal and gram-negative (Escherichia coli and Pseudomonas aeruginosa) isolates were assessed on three environmental surfaces: a non-nutrient surface, a woven cotton fiber, and a blood protein coagulum. The bacteria were dried on these surfaces and quantitatively subcultured over six months. The viability was consistently higher on dried blood surfaces. Viability was next highest on cotton strings. For both of these environments, staphylococci appeared to lose viability between three and six months, while E. coli and P. aeruginosa survived longer. Survival on a clean non-nutrient surface (tubes alone) for all organisms was much briefer and did not extend beyond four weeks. Such extended survival on blood and fiber surfaces, as observed in part, explains the difficulty in controlling colonization of patients by and spread of these nosocomial pathogens.


Spectrum of perforation peritonitis.
Perforation peritonitis mostly results from the perforation of a diseased viscus. Other causes of perforation include abdominal trauma, ingestion of sharp foreign body and iatrogenic perforation. The diagnosis is mainly based on clinical grounds. Plain abdominal X-rays (erect) may reveal dilated and oedematous intestines with pneumoperitoneum. Ultrasound and CT scan may diagnose up to 72% and 82% of perforation respectively. The present study was carried out to study various etiological factors, modes of clinical presentation, morbidity and mortality patterns of perforation peritonitis presented in the RIMS hospital, Imphal, India. The study was conducted from September 2010 to August 2012 on 490 cases of perforation peritonitis admitted and treated in the Department of Surgery. Initial diagnosis was made on the basis of detailed history, clinical examination and presence of pneumoperitoneum on erect abdominal X-ray. A total of 490 patients of perforation peritonitis were included in the study, with mean age of 48.28 years. 54.29% patients were below 50 years and 45.71% patients were above 50 years. There were 54.29% male patients and 45.71% female patients. Only 30% patients presented within 24 hours of onset of symptoms, 31.43% patients presented between 24 to 72 hours and 38.57% patients presented 72 hours after the onset of symptoms. Mean duration of presentation was 54.7 hours. Overall 469 patients were treated surgically and 21 patients were managed conservatively. Overall morbidity and mortality recorded in this study were 52.24% and 10% respectively.


The role of the ventral dentate gyrus in anxiety-based behaviors.
Dorsoventral lesion studies of the hippocampus (HPP) indicate that the dorsal axis is important for spatial processing and the ventral axis is important in anxiety and olfactory processes. There is some evidence that ventral CA3 and ventral CA1 subregions are important for cued retrieval in fear conditioning, which supports a ventral-anxiety relationship. However, the role of the ventral dentate gyrus (DG) in anxiety-based behaviors is less understood. Therefore, we used elevated plus and open field mazes to investigate the role of the ventral DG in the ability to modify behavior in potentially dangerous conditions and to clarify a few previous reports that ventral HPP lesions may induce hyperactivity. Rats with ventral DG lesions spent significantly more time in the open arms of the elevated plus maze and inner zone of the open field test than did controls and rats with dorsal DG lesions. Locomotor measures indicate that all rats traveled at similar rates in enclosed arms, as well as in open arms of the elevated plus maze and all groups traveled at similar rates in the open field test, which indicates that differences in exploration were not likely due to hyperactivity. The present study findings indicate that the ventral DG plays an important role in anxiety-based behaviors, such as preference for safer environments and the ability to modify exploratory behavior when in potentially dangerous environments and that the dorsal DG is not importantly involved in anxiety.


The influence of the supernatant obtained from a culture of IL-2-activated lymphocytes on human hematopoietic progenitors.
A supernatant obtained from the culture of recombinant human interleukin 2-activated lymphocytes was added to granulocyte (G)-, macrophage (M)-, and granulocyte-macrophage (GM)-progenitor assays using a plasma clot culture method. The supernatant was found to exert a suppressive influence on the colony and cluster formations of the G progenitors. This suppressive influence of the supernatant was almost completely neutralized by the addition of a combination of anti-human tumor necrosis factor alpha (HuTNF-alpha) and anti-human interferon gamma (HuIFN-gamma) antibodies, and it has been speculated that this suppressive influence of the supernatant is probably due to TNF-alpha and IFN-gamma. The numbers of M and GM progenitors increased remarkably in the assays in which the supernatant was added when compared to assays without the supernatant; this suggests that these progenitors were resistant to TNF-alpha and IFN-gamma. Among the bone marrow mononuclear cells (BMNC) excluding erythroid-rosette-forming (ERFC) or adherent cells, the influence of the supernatant on these progenitors was not significantly different. The results of our study have shown that ERFC and the adherent cells in BMNC hardly affected the appearance of the suppressive influence.


A review on the performance of osteoporosis self-assessment tool for Asians in determining osteoporosis and fracture risk.
The prevalence of osteoporosis in Asian countries is growing. An effective screening method will enable patients at risk for osteoporosis to receive early diagnosis and treatment, and avoid overcrowding the limited dual-energy x-ray absorptiometry (DXA) machines available in Asian countries. Many simple osteoporosis screening algorithms have been developed but they are not validated for use in Asian populations. osteoporosis self-assessment tools for Asians (OSTA), established using a multinational Asian cohort, is the first screening algorithm that caters for the Asian populations. It considers only body weight and age in the algorithm. It shows consistently high performance and sensitivity in identifying postmenopausal women at risk for osteoporosis in many Asian countries. Its usage has been expanded for identifying osteoporosis in men, as well as determining fracture risk for both sexes. However, the performance of OSTA is influenced by age, sex, ethnicity and site of BMD measurement to define osteoporosis. Its usage is also limited in individuals without apparent risk factors. These limitations should be noted by physicians considering the use of OSTA in clinical setting. As a conclusion, OSTA is a cost-effective measure for osteoporosis screening in primary healthcare setting.


A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia.
Ceftazidime/avibactam comprises the broad-spectrum cephalosporin ceftazidime and the non-β-lactam β-lactamase inhibitor avibactam. This phase 3, randomised, double-blind study (NCT01726023) assessed the efficacy and safety of ceftazidime/avibactam plus metronidazole compared with meropenem in patients with complicated intra-abdominal infection (cIAI) in Asian countries. Subjects aged 18-90 years and hospitalised with cIAI requiring surgical intervention were randomised 1:1 to receive every 8 h either: ceftazidime/avibactam (2000/500 mg, 2-h infusion) followed by metronidazole (500 mg, 60-min infusion); or meropenem (1000 mg, 30-min infusion). Non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was concluded if the lower limit of the 95% confidence interval (CI) for the between-group difference in clinical cure rate was greater than -12.5% at the test-of-cure (TOC) visit (28-35 days after randomisation) in the clinically evaluable (CE) population. Safety was also evaluated. Of 441 subjects randomised, 432 received at least one dose of study medication (ceftazidime/avibactam plus metronidazole, n = 215; meropenem, n = 217). In the CE population at the TOC visit, non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was demonstrated, with clinical cure reported for 93.8% (166/177) and 94.0% (173/184) of subjects, respectively (between-group difference, -0.2, 95% CI -5.53 to 4.97). The clinical cure rate with ceftazidime/avibactam plus metronidazole was comparable in subjects with ceftazidime-non-susceptible and ceftazidime-susceptible isolates (95.7% vs. 92.1%, respectively). Adverse events were similar between the study groups. Ceftazidime/avibactam plus metronidazole was non-inferior to meropenem in the treatment of cIAIs in Asian populations and was effective against ceftazidime-non-susceptible pathogens. No new safety concerns were identified.


Structure-activity relationships in 3-isothiazolones.
The biological activity of a series of structurally diverse 3-isothiazolones (1) has been assessed by evaluating the minimum inhibitory concentration required to inhibit the growth of E. Coli. The structure and electronic properties of these derivatives have been calculated using both semi-empirical and ab initio molecular orbital methods. Multi-linear regression analysis shows no correlation between the experimental activity of the 3-isothiazolones and either the calculated geometries, electronic properties, or the frontier orbital energies of these derivatives, but a reasonable relationship is found with other parameters including their calculated solvation energies, suggesting that diffusion may play an important role in their mode of action.


Sarcoidosis-associated hepatitis C virus infection.
Although several reports of sarcoidosis have been reported in hepatitis C virus (HCV)-infected patients treated with interferon-alpha, this association has never been described in nontreated HCV patients. We report two cases of sarcoidosis associated with chronic hepatitis C infection. The patients developed multivisceral sarcoidosis (cutaneous, lungs, nodes) at two and at least six years after the presumed date of infection. One patient obtained remission of sarcoidosis with corticosteroid treatment but the other remained corticodependent. The levels of hepatic enzymes were not significantly modified throughout the course of corticosteroid therapy. In conclusion, these case reports suggest that HCV itself could induce a granulomatous reaction in chronic HCV-infected patients through the stimulation of the cellular immune system. It could be of interest to test for HCV infection all patients diagnosed with sarcoidosis and to watch over every treated or nontreated hepatitis C infected patient for the development of granulomatous lesions.


Effect of hydroalcoholic extract of Echinacea purpurea in combination with meglumine antimoniate on treatment of Leishmania major-induced cutaneous leishmaniasis in BALB/c mice.
Progressive resistance of Leishmania parasite to available drugs including, meglumine antimoniate, has been reported from various regions of the world, especially Iran. This study was conducted to evaluate the effect of hydroalcoholic extract of Echinacea purpurea in a combination therapy with glucantime in the treatment of cutaneous leishmaniasis caused by Leishmania major. Hydroalcoholic extract of E. purpurea was prepared from the plant. Amastigote form of L. major was inoculated to the tail base of thirty mice. After their tails became wounded, mice were divided into six groups. The first group was used as control and the second group received 100 mg/kg of Echinacea extract (orally). The third group was treated by meglumine antimoniate with dose of 20 mg/kg. Combination therapy was used for group four, five, and six where the mice received a different concentration of extract (100-200 mg/kg) and glucantime (10-20 mg/kg). The size of the cutaneous lesion on tail base was measured regularly. Findings were analyzed by SPSS software and using Kruskal-Wallis test. The sizes of the lesion were increased in all mice of control group by the time. The mean size of lesions in mice receiving the extract and/or receiving the extract along with meglumine antimoniate was lower than those of control mice, but the differences were not statistically significant (P > 0.05). On the other hand, the differences between the group of mice which received meglumine antimoniate alone, and the rest of groups were statistically significant (P < 0.05). E. purpurea extract in doses which have been used in this study and combination with meglumine antimoniate was not much effective against L. major in BALB/C mice.


Interaction of HIV-1 integrase with DNA repair protein hRad18.
We have previously shown that human immunodeficiency virus-1 (HIV-1) integrase is an unstable protein and a substrate for the N-end rule degradation pathway. This degradation pathway shares its ubiquitin-conjugating enzyme, Rad6, with the post-replication/translesion DNA repair pathway. Because DNA repair is thought to play an essential role in HIV-1 integration, we investigated whether other molecules of this DNA repair pathway could interact with integrase. We observed that co-expression of human Rad18 induced the accumulation of an otherwise unstable form of HIV-1 integrase. This accumulation occurred even though hRAD18 possesses a RING finger domain, a structure that is generally associated with E3 ubiquitin ligase function and protein degradation. Evidence for an interaction between integrase and hRad18 was obtained through reciprocal co-immunoprecipitation. Moreover we found that a 162-residue region of hRad18 (amino acids 65-226) was sufficient for both integrase stabilization and interaction. Finally, we observed that HIV-1 integrase co-localized with hRad18 in nuclear structures in a subpopulation of co-transfected cells. Taken together, these findings identify hRad18 as a novel interacting partner of HIV-1 integrase and suggest a role for post-replication/translesion DNA repair in the retroviral integration process.


Paediatric primary care quality and accessibility: Parents' perspective.
To measure parents' satisfaction with paediatric primary care quality and accessibility. High-quality paediatric primary care is a cornerstone of efforts to improve health outcomes and access to care, as well as to control health care spending. A strong primary care infrastructure is related to improved health outcomes, including an improved mortality rate. A cross-sectional survey using the Parents' Perception of Primary Care questionnaire and evidence-based items from the Rourke Baby Record were used to measure parents' satisfaction. Of 200 questionnaires sent, 130 were returned. The mean number of children per family was 1.7+/-0.8 (mean +/- SD). Sixty-six per cent of children received their primary care from general practitioners, 19% received their primary care from paediatricians, and 15% had no regular physician and identified other professionals (community nurses, midwives or chiropractors) as their primary care providers. Parents were questioned about their child's hearing in 66% of cases. Only 41% of parents received guidance about breastfeeding, 37% about adequate sleeping position, 17% about the dangers of second-hand smoke and 16% about car safety seats. The level of satisfaction with communication, contextual knowledge and coordination of care was higher for families followed by general practitioners and paediatricians than for families followed by nonphysicians. According to the Parents' Perception of Primary Care scores, the overall satisfaction with primary care was higher for care given by general practitioners and paediatricians than for care given by midwives or chiropractors, and intermediate when given by nurses. In this survey, the majority of children received their primary care from physicians, most commonly general practitioners. Parents' overall satisfaction regarding their infant's primary health care was higher when it was delivered by physicians than by alternative health care providers. Evidence-based guidance recommendations were rarely followed.


Dapagliflozin in the treatment of patients with heart failure with reduced left ventricular ejection fraction - a practical approach.
Because of its frequent occurrence, poor prognosis, low quality of life of patients accompanying the disease and high costs associated with treatment heart failure is a significant health problem in modern cardiology. The treatment of patients with heart failure and reduced ejection fraction (HFrEF) is supported by large-scale randomized clinical trials (RCTs), reflected in the ESC/HFA treatment recommendations. The use of β-blockers, inhibitors of the renin-angiotensin aldosterone system (RAA), including angiotensin converting enzyme ACE/ARB inhibitors, angiotensin and neprilysin receptor blockers (ARNI) and mineralocorticoid receptor antagonists (MRA) have been a solid basis for triple HFrEF therapy over the last few years, partially altering the natural history of patients with HF. Despite this, the 5-year survival rate in HF is still lower than for some types of cancer. Therefore, the search for new drugs to improve the prognosis of this disease is still ongoing. A new group of drugs - the so-called flozins, i.e. - is a great hope for a change in the natural history of heart failure. The following article presents practical aspects of using these drugs in the treatment of patients with HFrEF, taking into account both the inclusion criteria and various clinical profiles of patients.


A comparison study of Fenton-like and Fenton reactions in dichloromethane removal.
Dichloromethane (DCM), as a low-chlorinated organic compound, is hardly to be degraded through the reductive dechlorination pathway. In this study, the removal of DCM in Fenton-like system, using activated carbon fibres-supported zero-valence Fe/Ni nanoparticles (ACF-Fe/Ni) as catalysts, was investigated and compared with that of a traditional Fenton system (Fe2+/H2O2). The influence of vital parameters, including initial solution pH, DCM concentration, catalyst and H2O2 dosages, temperature and cosolute on the removal of DCM, was systematically studied. The results showed that 94.2% of DCM with an initial concentration of 5 mg/L could be removed in the Fenton-like reaction under the optimum condition: initial pH of 2.0, 0.4 g/L of ACF-Fe/Ni, 10 mM of H2O2 and a temperature of 30°C. In comparison, the removal of DCM in the Fenton-like system was faster than that of the Fenton system and the corresponding activation energies were 39.69 and 33.82 kJ/mol, respectively. The coexistence of solute was adverse to the removal of DCM in both Fenton-like and Fenton systems. Moreover, the active species for DCM removal in the Fenton-like system was confirmed as hydroxyl radical (·OH) via the quenching experiment and electron paramagnetic resonance measurement. The incomplete mineralisation (41.7%) of DCM after reaction indicated that the Fenton-like technology had the potential to realise DCM's non-toxic and harmless conversion and organic intermediates formed needed to take longer time to be decomposed.


Monoclonal antibody to mouse lipopolysaccharide receptor protects mice against the lethal effects of endotoxin.
Specific endotoxic lipopolysaccharide (LPS) binding sites on the cell membranes of murine lymphocytes and macrophages that may serve as functional receptors for LPS have recently been identified using photoactivatable cross-linking LPS derivatives. A monoclonal antibody (Mab 5D3) with specificity for this 80-kDa protein has also been generated and characterized. The capacity of MAb 5D3 to protect mice against the lethal effects of endotoxin was investigated. Pretreatment of CF1 mice with as little as 15 micrograms of MAb 5D3 provided virtually complete protection against a dose of endotoxin 10-fold greater than that required to kill all mice in an untreated control group using the galactosamine sensitization model. Significant protection was also afforded normal mice given MAb 5D3 relative to saline. Several lines of evidence suggest that MAb 5D3-mediated protection is due to the agonist properties of this antibody rather than a receptor blockade mechanism.


[Pharmacological studies of nin jion pei pa koa].
The results showed that King To Nin Jiom Pei Pa Koa had significant cough relieving and sputum removing effects. It also had an evident effect on relieving asthma in vivo and in vitro. In four acute or sub-acute inflammatory models, the anti-inflammatory effect was marked.


Plasma radioiron kinetics in man: explanation for the effect of plasma iron concentration.
The plasma iron turnover was measured in 19 normal subjects. A correlation was found between plasma iron concentration and plasma iron turnover. In addition to the turnover of 55Fe at normal plasma iron concentration (predominantly monoferric transferrin), a second turnover in which the labeled plasma was saturated with iron (to produce predominantly diferric transferrin) was studied with 50Fe. It was demonstrated that diferric transferrin had a greater rate of iron turnover but that the distribution between erythroid and non-erythroid tissues was unchanged. It was concluded that plasma iron turnover is dependent on the monoferric/diferric transferrin ratio in the plasma but that the internal distribution of iron is unaffected.


Age-Dependent Modification of Intracellular Zn2+ Buffering in the Hippocampus and Its Impact.
The basal concentrations of extracellular Zn2+ and intracellular Zn2+, which are approximately 10 nM and 100 pM, respectively, in the brain, are markedly lower than those of extracellular Ca2+ (1.3 mM) and intracellular Ca2+ (100 nM), respectively, resulting in much less attention paid to Zn2+ than to Ca2+. However, intracellular Zn2+ dysregulation, which is closely linked with glutamate- and amyloid β-mediated extracellular Zn2+ influx, is more critical for cognitive decline and neurodegeneration than intracellular Ca2+ dysregulation. It is estimated that the age-dependent increase in the basal concentration of extracellular Zn2+ in the hippocampus plays a key role in cognitive decline and neurodegeneration. The characteristics of extracellular Zn2+ influx in the hippocampus may be modified age-dependently, probably followed by modification of intracellular Zn2+ buffering that is closely linked with age-related cognitive decline and neurodegeneration. Reduction of intracellular Zn2+-buffering capacity may be linked with the pathophysiology of progressive neurodegeneration such as Alzheimer's disease. This paper deals with age-dependent modification of intracellular Zn2+ buffering in the hippocampus and its impact. On the basis of the estimated impact, we propose a potential defense strategy against Zn2+-mediated neurodegeneration, i.e., metallothionein induction in the hippocampus.


Regional comparison of preoperative biometry for cataract surgery between two domestic institutions.
Regional variations of the preoperative biometry can affect the refractive accuracy of cataract surgery. We aimed to compare the preoperative biometric data for cataract surgery between two domestic institutions. We retrospectively reviewed the preoperative biometric data of 673 consecutive eyes undergoing standard cataract surgery at Miyata Eye Hospital (Miyazaki; M group) and Kitasato University Hospital (Kanagawa; K group), and compared these data between the two groups. We found significant differences in the mean keratometric readings (44.39 ± 1.56 D vs. 44.09 ± 1.74 D) (unpaired t test, p = 0.034), the anterior chamber depth (3.14 ± 0.43 mm vs. 3.46 ± 0.62 mm) (p < 0.001), the axial length (23.98 ± 1.62 mm vs. 24.59 ± 1.82 mm) (p < 0.001), and the lens thickness (4.64 ± 0.48 mm vs. 4.37 ± 0.62 mm) (p < 0.001), in the M and K groups, respectively. Otherwise, we found no significant differences in corneal astigmatism (p = 0.104), or central corneal thickness (p = 0.480) between the two groups. For subgroup analysis, the prediction error (0.06 ± 0.47 D) in the M group was significantly more hyperopic than that (- 0.09 ± 0.54 D) in the K group (p = 0.006). There were significant differences in the mean keratometric readings, the anterior chamber depth, the axial length, and the lens thickness, by approximately 0.3 D, 0.3 mm, 0.6 mm, and 0.3 mm, respectively. Regional variations of the preoperative biometry did exist to some extent, and were not clinically negligible, in consideration of the precise IOL power calculation and the subsequent refractive accuracy of cataract surgery. University Hospital Medical Information Network Clinical Trial Registry (000037994).


Simple Method for High-Sensitivity Determination of Cosmogenic 35S in Snow and Water Samples Collected from Remote Regions.
Cosmogenic 35S is useful in understanding a wide variety of chemical and physical processes in the atmosphere, the hydrosphere, and the cryosphere. The 87.4-day half-life and the ubiquity of sulfur in natural environments renders it an ideal tracer of many phenomena. Measurements of 35S in snow and water samples are scarce as existing analytical methods require a large volume of sample (>20 L) due to their high analytical activity background and low counting efficiency. Here, we present a new set of snow/water sample collecting and handling procedures for high-sensitivity determination of cosmogenic 35S using a low-level liquid scintillation spectrometer. Laboratory experiments using diluted 35S standards (with activities of <5 disintegrations per minute) showed a 35S recovery percentage of ∼95%, demonstrating a relatively small deviation from the true value. Using this method, we successfully measured 35S in ∼1 L of fresh snow sample collected from a glacier on the Tibetan Plateau to be 47 ± 7 mBq/L. On the basis of 35S activities in 9 natural samples measured in this study, a first proof-of-concept approximation for age determinations and source attributions was presented. This new method will provide a powerful tool in studying 35S in small volumes of snow and water samples, especially those from remote but climatically important regions such as the polar regions and the Tibetan Plateau and Himalayas. The measurements are particularly important as the radioactive sulfur provides an actual clock of glacial melting processes. With the growing rate of glacial loss, the need for measurements from remote locations becomes all the more important.


Validation Study of the Malay version of the Neuropsychiatric Inventory.
There is a lack of local instruments to assess behavioural and psychological symptoms of dementia (BPSD). This 2-stage cross-sectional study was aimed at validating a Malay translated version of the Neuropsychiaric Inventory (MvNPI). It was conducted on a selected group of 138 elderly outpatients with dementia and their caregivers in Hospital Pulau Pinang. Severity of dementia was assessed using the Malay-translated version of Mini Mental State Examination (MMSE). The original NPI was translated and then back-translated before it was pilot-tested. The MvNPI was administered twice, a week apart on the same caregiver by the same investigator. The individual items and total scale score of MvNPI had high internal consistency, with Corrected Item-Total Correlation ranging from satisfactory to good (0.41 to 0.77). The Cronbach's alpha for all the NPI domains showed high internal consistency (0.83), and subtotal for severity and distress scores were perfect (0.998 to 1.00). There was no significant difference between test-retest mean scores (p>0.05) and their correlations were perfect (0.996 to 1.00). Content validity indicated mild and inverse relationship between MMSE scores and severity, and distress score (-0.281 and -0.268, respectively, with p<0.001). Discriminant validity calculated using Mann-Whitney U test was found to be significant (p<0.001) in differentiating severity of cognitive impairment. Factor analysis revealed four possible components existed in MvNPI. The MvNPI is a valid and reliable tool for assessing BPSD among Malay speaking populations of Malaysia and its neighbouring South East Asian countries.


Cyclooxygenase inhibition causes marked impairment of renal function in elderly subjects treated with diuretics and ACE-inhibitors.
Treatment with angiotensin-converting enzyme (ACE)-inhibitors is known to cause an initial reduction in glomerular filtration rate (GFR) in patients with congestive heart failure. The long-term beneficial effects of ACE-inhibitors in these patients can be counteracted by cyclooxygenase-inhibitors. To quantify the negative renal effects of the cyclooxygenase-inhibitor diclofenac in elderly healthy subjects and to assess how treatment with an ACE-inhibitor, after activation of the renin-angiotensin system, influences these renal effects. Fourteen elderly, healthy subjects received oral diclofenac and placebo in a double-blind cross-over fashion. The study was divided in two parts; in part one, subjects received no pre-treatment and in part two, the subjects were given pre-treatment with bendroflumethiazide and enalapril in order to activate the renin-angiotensin system. Diclofenac induced significant (p<0.05) decreases in GFR, urine flow, excretion rates of sodium and potassium, electrolyte clearance, osmolality clearance and free water clearance both with and without renin-angiotensin system activation. Least square means (95% CI) of all observations during the first 6 h after dosing showed that diclofenac caused a reduction in GFR from 71 (64-78) to 59 (52-66) ml/min. After pre-treatment, diclofenac further reduced GFR from 60 (52-67) to 48 (40-55) ml/min. After diclofenac administration, urine flow fell from 7.4 (6.4-8.3) to 5.1 (4.2-6.1) ml/min, after pre-treatment, diclofenac gave a further reduction from 4.1 (3.1-5.1) to 2.2 (1.3-3.2) ml/min. More than half of the reductions were caused by the pre-treatment. Renal function in elderly, healthy subjects is impaired after acute intake of diclofenac. This impairment is observed both with and without activation of the renin-angiotensin system and ACE-inhibitor treatment but is more pronounced after pre-treatment.


Blended psychosocial support for partners of patients with ALS and PMA: results of a randomized controlled trial.
Objective: To evaluate whether a blended (face-to-face and online) psychosocial support program for caregivers of patients with Amyotrophic Lateral Sclerosis (ALS) and Progressive Muscular Atrophy (PMA), aimed at enhancing feeling of control over caregiving, reduces psychological distress. Methods: A randomized controlled trial using a wait-list control design was conducted. Caregiver-patient dyads were randomly assigned to either the support program (n = 74) or to a wait-list control group (n = 74). The support program, based on Acceptance and Commitment Therapy, consists of 1 face-to-face contact, 6 online guided modules and 1 telephone contact. Participants filled in questionnaires at baseline, 3 and 6 months. Caregivers' feeling of control over caregiving was assessed using two self-efficacy measures. Primary outcome was caregivers' psychological distress. Secondary outcomes included caregiver burden, caregiver quality of life and patients' quality of life and psychological distress. Intention-to-treat and per-protocol analyses were performed using linear mixed models. Results: The support program had no effect on the primary or secondary outcomes, despite a significant positive effect on the intervening variable self-efficacy with regard to control over thoughts. Almost half of the caregivers did not complete the intervention with the most frequently reported reason being lack of time. Caregivers who completed the intervention evaluated the support program positively. Conclusions: The support program did not reduce distress of partners of patients with ALS/PMA but may be beneficial by increasing feeling of control over the caregiving situation. The high level of intervention drop outs may have limited the ability to detect an intervention effect.Trial registration: Netherlands Trial Registry NTR5734, registered 28 March 2016.


[Two cases of Kallmann's syndrome].
Herein we report two cases of hypogonadism with anosmia or hyposmia (Kallmann's syndrome), a 23-year-old single man (case 1) and a 34-year-old single man. (case 2). Micropenis and small testes were seen in both cases. Central anosima and central hyposmia were found in cases 1 and 2, respectively. Their karyotypes were normal (46, XY). The plasma levels of LH and FSH were low and the reaction to LH-RH test was poor in both cases. After repetitious LH-RH administrations, a good response of plasma LH was recognized in both cases except for a poor response of plasma FSH in case 1, while plasma testosterone remained low in both cases. Their testicular biopsies revealed immature testes without any developed Sertoli and Leydig cells.


Key concepts of demand-driven health care; an approach based on client's needs.
In most European countries we are witnessing a shift from supply-driven to demand-driven approaches in health care. According to these approaches, health care should contribute to the fulfillment of health-care-related needs of individuals and, therefore, to their perceived quality of life. The purpose of this study is to develop a conceptual framework for research in this new view of health care. The authors conclude that the 'felt need' should be the foundation of demand-driven care. The second part of the study is based on a widely used behavioral model resulting in a conceptual framework for research, policy and practice. This study makes a start at providing information about fundamental concepts that are at the heart of the demand-driven approach. In order to contribute to quality of life, health care providers should explore the underlying needs while developing services in order to fit the demand-driven approach.


Resistance of aphis gossypii (Homoptera: Aphididae) to fenvalerate and imidacloprid and activities of detoxification enzymes on cotton and cucumber.
Resistance of two strains of cotton aphid, Aphis gossypii Glover, to fenvalerate and imidacloprid were determined on cotton (Gossypium hirsutum L.) and cucumber (Cucumis sativa L.) after resistance selection of one strain to fenvalerate for 16 consecutive generations, and of a second strain to imidacloprid for 12 consecutive generations on cotton in greenhouses. Dose-response and activities of detoxication enzymes of the fenvalerate-resistant strain (R-fenvalerate), the imidacloprid-resistant strain (R-imidacloprid), and a susceptible strain (S) were determined. After 16 consecutive generations of selection, resistance of A. gossypii to fenvalerate increased >29,000-fold and to imidacloprid 8.1-fold. On cucumber. resistance of the R-fenvalerate strain to fenvalerate increased 700-fold and to imidacloprid 3.6-fold. However, the most significant finding in this study was that the R-imidacloprid strain exhibited cross-resistance to fenvalerate, with a resistance ratio of 108.9-fold on cotton and 3:3.5-fold on cucumber, whereas the R-fenvalerate strain did not show significant cross-resistance to imidacloprid on either plant species. Both resistant strains of A. gossypii were more resistant to fenvalerate on cotton than on cucumber, whereas their susceptibility to imidacloprid on otton and cucumber were not significantly different. The response of the S strain to fenvalerate and imidacloprid were similar on cotton and Cucumber. Activities of acetylcholinesterase (AChE) and alpha-naphthylacetate (alpha-NA) esterases of A. gossypii were significantly different among the three strains, with the R-fenvalerate strains having the highest, followed by the R-imidacloprid strain, and the S strain the lowest. The activities of the AChE and alpha-NA esterases for all three strains were also significantly higher on cotton than on cucumber. The resistance mechanism and resistance management strategies for the R-fenvalerate and R-imidacloprid strains of A. gossypii to fenvalerate and imidacloprid on cotton and cucumber are discussed.


Caution Before Embracing Team Mentoring in Academic Medical Research Training: Recommendations from a Qualitative Study.
Background: Multidisciplinary team mentoring increasingly is being advocated for biomedical research training. Before implementing a curriculum that could include team mentoring, we asked faculty about their opinions of this mentoring approach. Questions/Purposes: The goals of this study were to ask faculty about the benefits, challenges, and drawbacks of team mentoring in research training. Methods: Twenty-two experienced mentors representing all academic departments at a single institution were interviewed about perceived benefits, drawbacks, and their willingness to participate in team mentoring. Responses were analyzed with qualitative techniques using grounded theory and a comparative analytic strategy. Results: Faculty noted academic pursuits in medicine usually occur within, and not across, specialties; thus, multidisciplinary team mentoring would require coordinating diverse work schedules, additional meetings, and greater time commitments. Other challenges included ensuring breadth of expertise without redundancy, skillfully managing group dynamics, and ensuring there is one decision-maker. Potential drawbacks for mentees included reluctance to voice preferences and forge unique paths, perceived necessity to simultaneously please many mentors, and less likelihood of establishing a professional bond with any particular mentor. Conclusions: Faculty recommended caution before embracing team mentoring models. An acceptable alternative might be a hybrid model with a primary mentor at the helm and a selected group of co-mentors committed to a multidisciplinary effort. This model requires training and professional development for primary mentors.


Prevalence of Aminotransferase Macroenzymes in Rheumatoid Arthritis Patients and Impact on Their Management.
Rheumatoid arthritis (RA) treatment can be hepatotoxic, but liver enzymes can be falsely elevated due to macroenzyme presence. Macroenzymes are often found in autoimmune diseases, but prevalence and effect on treatment is unclear. This study aimed to determine aminotransferase macroenzyme prevalence and effect in RA patients. This study included consecutive RA patients without liver disease sent for laboratory tests. Samples with elevated AST or ALT were processed for macroenzymes. Presence was determined using polyethylene glycol precipitation (PEG). Out of 126 patients, 21 had elevated aminotransferase levels. Due to liver disease, 6 patients were excluded, another 3 were unavailable for informed consent, leaving 12 patients for inclusion. Out of 12 patients, 1 had increased AST levels, 2 increased ALT levels, and 9 both. Macro-ALT was detected in 5/11 patients, 1 also had macro-AST. Out of 5 patients with macroenzymes, treatment change was seen in 3/5 patients, imaging in 2/5, both in 2/5. Elevated liver enzymes in RA patients is not always indicative of hepatotoxicity, as shown by the fact that about half of patients in our study had macroenzymes detected. Before assuming drug hepatotoxicity and changing treatment or ordering imaging, rheumatologists could consider macroenzyme presence.


Recombination, interference and sequence: comparison of chromosomes 21 and 22.
The euchromatic regions of chromosomes 21 and 22 are almost completely sequenced and have similar lengths (33.7-34.6 Mb). This similarity effectively controls for the influence of length, making comparisons of recombination and interference interesting. For both chromosomes, there is less male than female recombination, and male recombination is associated with GT/CA repeats. The striking sex difference may result from greater condensation of chromosomes in paternal meiosis, possibly restricting recombination to regions with longer repeat tracts and/or higher repeat densities. Chiasma interference in both sexes for chromosome 22 and in females for chromosome 21 is close to the genome average. Chromosome 21 is significantly different in male meiosis, with near complete interference, suggesting that even when double recombinants occur they are widely spaced. We propose that this difference is related to the different distribution of GT/CA dinucleotides. These repeats are widely distributed on chromosome 22, perhaps offering greater opportunities for double recombinants to occur within smaller regions, whereas they are largely subtelomeric in distribution on chromosome 21.


Differential carbohydrate metabolism conducts morphogenesis in embryogenic callus of Hevea brasiliensis (Müll. Arg.).
Somatic embryogenesis in Hevea is stimulated when the embryogenesis induction medium contains maltose, rather than glucose, fructose, or sucrose, in equimolarity (Blanc et al., 1999). Kinetic analyses were carried out on various physiological and biochemical indicators over the 8 weeks that the induction phase then expression of somatic embryogenesis can take. Embryogenesis induction in the presence of glucose, fructose or sucrose revealed strong callus growth in the first 3-4 weeks, associated with a high intra- and extracellular hexose content, a high starch content and a substantial decline in protein synthesis. In the presence of maltose, callus growth was slow and only half that seen with sucrose. This morphogenetic behaviour is associated with a drop in endogenous hexose and starch contents, and an increase in protein synthesis in the first three weeks of culture. The induction of embryogenesis in the presence of maltose was uniform and twice as fast as with sucrose supply. At the end of culture, peroxidase activity, antioxidant and membrane protein contents increased in these calluses; these characteristics may be associated with somatic embryo organization and with the maintenance of effective membrane integrity within a nutrient environment that has become limiting. These new results tally with data in the literature on the roles of sugars, and provide some precise information with regard to the 'carbohydrate deficit' hypothesis usually put forward to explain maltose action. An analysis of these results led to the hypothesis that regulation of endogenous hexose contents at a low level, through slow maltose hydrolysis, was a key element of the biochemical signal leading this callus towards somatic embryogenesis.


Synthesis of catecholamines in the developing spinal cord of the rat.
Using mass fragmentographic techniques, the synthesis of dopamine (DA) and norepinephrine (NE) was studied in five functional regions in the spinal cord of the developing rat. Norepinephrine was first detectable in the whole cord on fetal day (FD) 16. Thereafter, there was a rapid increase in synthesis. The fastest rate occurred in the ventral horn. The peak concentration was recorded in the latter half of neonatal life, followed by a decline back to the levels found in the adult cord. The capacity of the developing cord to synthesize NE from injected L-dihydroxyphenylalanine (L-DOPA) increased in concert with its normal synthetic capacity. There was no clear consistent pattern in the development of DA synthesis, with two exceptions: (1) in the cervical dorsal horn (CDH), cervical ventral horn ( CVH ), and thoracic zona intermedia ( TZI ), there was a peak of DA on the day of birth; (2) in all regions there was a peak of DA on neonatal day (ND) 20. At FD 16 (the earliest time studied) the developing cord was capable of considerable synthesis (6.0 nmol/g) of DA from injected L-DOPA. This synthetic capacity developed rapidly, peaked at ND 4, and declined back to the adult levels by ND 20. Control experiments indicate that only about 10% (at best) of the DA synthesized from injected L-DOPA occurs in monoaminergic nerve terminals. Norepinephrine is synthesized exclusively in noradrenergic nerve terminals. The newly synthesized DA and NE are both extensively metabolized in the cord. The results are discussed in relationship to current attempts to understand the functional importance of spinal monoaminergic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)


Endotoxin enhancement of toxic shock syndrome toxin 1-induced secretion of interleukin 1 by murine macrophages.
The purpose of this study was to determine whether endotoxin could augment toxic shock syndrome toxin 1 (TSST-1)-induced production of interleukin 1 (IL-1) by murine macrophages. Macrophages from C3H/HeJ or C57Bl/6 mice were stimulated with purified TSST-1 alone or in combination with lipopolysaccharide (LPS). A dramatic synergistic thymocyte-proliferative response was induced by supernatants from C57Bl/6 macrophages stimulated with both TSST-1 and LPS. No enhanced response was induced by supernatants from C3H/HeJ macrophages. A portion of the enhanced response induced by C57Bl/6 macrophage supernatants was attributed to synergism between IL-1 and residual TSST-1 in the thymocyte assay. The addition of monoclonal antibody to TSST-1 to the supernatants eliminated the effects of residual TSST-1 in the thymocyte assay and demonstrated a synergistic induction of IL-1. These data (1) show that LPS can enhance macrophage responsiveness to TSST-1; (2) suggest that TSST-1 not only induces IL-1 secretion but also enhances target cell responsiveness to IL-1; and (3) further support the role of IL-1 in the pathogenesis of toxic shock syndrome.


Effect of wall compliance and permeability on blood-flow rate in counter-current microvessels formed from anastomosis during tumor-induced angiogenesis.
Tumor blood-flow is inhomogeneous because of heterogeneity in tumor vasculature, vessel-wall leakiness, and compliance. Experimental studies have shown that normalization of tumor vasculature by antiangiogenic therapy can improve tumor microcirculation and enhance the delivery of therapeutic agents to tumors. To elucidate the quantitative relationship between the vessel-wall compliance and permeability and the blood-flow rate in the microvessels of the tumor tissue, the tumor tissue with the normalized vasculature, and the normal tissue, we developed a transport model to simultaneously predict the interstitial fluid pressure (IFP), interstitial fluid velocity (IFV) and the blood-flow rate in a counter-current microvessel loop, which occurs from anastomosis in tumor-induced angiogenesis during tumor growth. Our model predicts that although the vessel-wall leakiness greatly affects the IFP and IFV, it has a negligible effect on the intravascular driving force (pressure gradient) for both rigid and compliant vessels, and thus a negligible effect on the blood-flow rate if the vessel wall is rigid. In contrast, the wall compliance contributes moderately to the IFP and IFV, but significantly to the vessel radius and to the blood-flow rate. However, the combined effects of vessel leakiness and compliance can increase IFP, which leads to a partial collapse in the blood vessels and an increase in the flow resistance. Furthermore, our model predictions speculate a new approach for enhancing drug delivery to tumor by modulating the vessel-wall compliance in addition to reducing the vessel-wall leakiness and normalizing the vessel density.


Nuclear magnetic resonance studies on experimental malignant bone tumors.
The relaxation times of water protons were studied by nuclear magnetic resonance (NMR) method in two kinds of experimental malignant bone tumors, intramedullary transplanted VX2 carcinoma and Gardner osteosarcoma 519. The relaxation times for malignant tumor tissues were significantly elevated than those for normal bone tissues. Bone marrow sample, where VX2 carcinoma was transplanted 1 week before and included only a few scattered malignant tumor cells, showed the elevation in the relaxation times compared with that of normal bone marrow. In addition, analyses of the electrolytes and the water content of each tissue suggest that the elevation of the relaxation times is not necessarily attributable to the factor of the water content.


Childhood abuse and age at menarche.
Physical and sexual abuse are prevalent social hazards. We sought to examine the association between childhood physical and sexual abuse and age at menarche. Among 68,505 participants enrolled in the Nurses' Health Study II, we investigated the association between childhood physical abuse and sexual abuse and menarche before age 11 years (early) or after age 15 years (late) using multivariate logistic regression analysis, mutually adjusting for both types of abuse. Fifty-seven percent of respondents reported some form of physical or sexual abuse in childhood. We found a positive dose-response association between severity of sexual abuse in childhood and risk for early menarche. Compared with women who reported no childhood sexual abuse, the adjusted odds ratio (AOR) for early menarche in women who reported childhood sexual abuse was 1.20 (95% confidence interval [CI]: 1.10, 1.37) for sexual touching and 1.49 (95% CI: 1.34, 1.66) for forced sexual activity. Severe physical abuse predicted early menarche (AOR = 1.22, 95% CI: 1.10, 1.37). Childhood physical abuse had a dose-response association with late age at menarche: AOR 1.17 (95% CI: 1.04, 1.32) for mild, 1.20 (95% CI: 1.08, 1.33) for moderate, and 1.50 (95% CI: 1.27, 1.77) for severe physical abuse. Sexual abuse was not associated with late menarche. Childhood abuse was prevalent in this large cohort of U.S. women. Severity of childhood sexual abuse was associated with risk for early onset of menarche, and physical abuse was associated with both early and late onset of menarche.


Temporal organization of English clear and conversational speech.
This study investigated the effect of hyperarticulated, intelligibility-enhancing clear speech on temporal characteristics as reflected in number, durations, and variability of consonant and vowel intervals in sentence- and paragraph-length utterances. The results of sentence-in-noise listening tests showed a consistent clear speech intelligibility gain across the utterances of varying complexity indicating that the talkers successfully maintained clear speech articulatory modifications throughout longer stretches of speech. The acoustic analysis revealed that some temporal restructuring accompanied changes in speaking style. This temporal restructuring was observed in the insertion of consonant and vowel segments that were dropped or coarticulated in conversational speech and in an increase in the number of prosodic phrases for clear speech. Importantly, coefficients of variation (variation of consonantal and vocalic intervals normalized for changes in speaking rate) for both consonantal and vowel intervals remained stable in the two speaking styles. Overall, these results suggest that increased intelligibility of clear speech may be attributed to prosodic structure enhancement (increased phrasing and enhanced segmentability) and stable global temporal properties.


Immunological analysis of treatment interruption after early highly active antiretroviral therapy.
We longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). After treatment interruption (TI), some individuals could maintain a low plasma viral load (<15,000 copies/mL), whereas others could not (>50,000 copies/mL). Before HAART was initiated, plasma viral load was similar. After TI, the numbers of CD8(+) T cells increased more in individuals without viral control, whereas individuals maintaining a low viral load showed a more pronounced increase in HIV-specific CD8(+) T-cell numbers. No differences were seen in the number or percentage of cytokine-producing HIV-1-specific CD4(+) T cells, or in proliferative capacity of T cells. Four weeks after TI, the magnitude of the total HIV-1-specific CD8(+) T-cell response (IFN-γ(+) and/or IL-2(+) and/or CD107a(+)) was significantly higher in individuals maintaining viral control. Degranulation contributed more to the overall CD8(+) T-cell response than cytokine production. Whether increased T-cell functionality is a cause or consequence of low viral load remains to be elucidated.


Antibiotic prophylaxis for wound infections in total joint arthroplasty: a systematic review.
We reviewed systematically the published evidence on the effectiveness of antibiotic prophylaxis for the reduction of wound infection in patients undergoing total hip and total knee replacement. Publications were identified using the Cochrane Library, MEDLINE, EMBASE and CINAHL databases. We also contacted authors to identify unpublished trials. We included randomised controlled trials which compared any prophylaxis with none, the administration of systemic antibiotics with that of those in cement, cephalosporins with glycopeptides, cephalosporins with penicillin-derivatives, and second-generation with first-generation cephalosporins. A total of 26 studies (11 343 participants) met the inclusion criteria. Methodological quality was variable. In a meta-analysis of seven studies (3065 participants) antibiotic prophylaxis reduced the absolute risk of wound infection by 8% and the relative risk by 81% compared with no prophylaxis (p < 0.00001). No other comparison showed a significant difference in clinical effect. Antibiotic prophylaxis should be routine in joint replacement but the choice of agent should be made on the basis of cost and local availability.


Long-term droughts may drive drier tropical forests towards increased functional, taxonomic and phylogenetic homogeneity.
Tropical ecosystems adapted to high water availability may be highly impacted by climatic changes that increase soil and atmospheric moisture deficits. Many tropical regions are experiencing significant changes in climatic conditions, which may induce strong shifts in taxonomic, functional and phylogenetic diversity of forest communities. However, it remains unclear if and to what extent tropical forests are shifting in these facets of diversity along climatic gradients in response to climate change. Here, we show that changes in climate affected all three facets of diversity in West Africa in recent decades. Taxonomic and functional diversity increased in wetter forests but tended to decrease in forests with drier climate. Phylogenetic diversity showed a large decrease along a wet-dry climatic gradient. Notably, we find that all three facets of diversity tended to be higher in wetter forests. Drier forests showed functional, taxonomic and phylogenetic homogenization. Understanding how different facets of diversity respond to a changing environment across climatic gradients is essential for effective long-term conservation of tropical forest ecosystems.


Thermoresponsive artificial extracellular matrix: N-isopropylacrylamide-graft-copolymerized gelatin.
Poly(N-isopropylacrylamide)-graft-copolymerized gelatin (PNIPAM-gelatin) was prepared by iniferter-based photopolymerization of multiply derivatized dithiocarbamylated gelatin. PNIPAM-gelatins exhibited low critical solution temperature (LCST) immediately below the physiological temperature. PNIPAAm-gelatin-coated dishes induced cell adhesion at 37 degrees C but incomplete detachment at room temperature, whereas dishes coated with PNIPAM or a mixture of PNIPAAm and gelatin showed little cell adhesion. The mixture of PNIPAAm-gelatin and PNIPAAm induced cell adhesion at 37 degrees C and detachment at 20 degrees C: the degrees of cell adhesion and detachment depended on the mixed ratio of PNIPAAm-gelatin and PNIPAAm. Complete thermoresponsive adhesion and detachment were found for the mixture containing a small fraction of PNIPAAm-gelatin (approximately 5 wt% with respect to PNIPAAm; gelatin content in the mixture is 2.7 wt%). Such a mixture may serve as thermoresponsive cell matrix for fabrication of a tissue-engineered device.


Management algorithms for cervical cancer screening and precancer treatment for resource-limited settings.
Management algorithms for screen-positive women in cervical cancer prevention programs have undergone substantial changes in recent years. The WHO strongly recommends human papillomavirus (HPV) testing for primary screening, if affordable, or if not, then visual inspection with acetic acid (VIA), and promotes treatment directly following screening through the screen-and-treat approach (one or two clinic visits). While VIA-positive women can be offered immediate ablative treatment based on certain eligibility criteria, HPV-positive women need to undergo subsequent VIA to determine their eligibility. Simpler ablative methods of treatment such as cryotherapy and thermal coagulation have been demonstrated to be effective and to have excellent safety profiles, and these have become integral parts of new management algorithms. The challenges faced by low-resource countries are many and include, from the management perspective, identifying an affordable point-of-care HPV detection test, minimizing over-treatment, and installing an effective information system to ensure high compliance to treatment and follow-up.


HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast activation and hypertrophic scar formation.
Transforming growth factor-β (TGF-β) signaling plays a key role in excessive fibrosis. As a class IIa family histone deacetylase (HDAC), HDAC5 shows a close relationship with TGF-β signaling and fibrosis. However, the effect and regulatory mechanism of HDAC5 in hypertrophic scar (HS) formation remain elusive. We show that HDAC5 was overexpressed in HS tissues and depletion of HDAC5 attenuated HS formation in vivo and inhibited fibroblast activation in vitro. HDAC5 knockdown (KD) significantly downregulated TGF-β1 induced Smad2/3 phosphorylation and increased Smad7 expression. Meanwhile, Smad7 KD rescued the Smad2/3 phosphorylation downregulation and scar hyperplasia inhibition mediated by HDAC5 deficiency. Luciferase reporter assays and ChIP-qPCR assays revealed that HDAC5 interacts with myocyte enhancer factor 2A (MEF2A) suppressing MEF2A binding to the Smad7 promoter region, which results in Smad7 promoter activity repression. HDAC4/5 inhibitor, LMK235, significantly alleviated hypertrophic scar formation. Our study provides clues for the development of HDAC5 targeting strategies for the therapy or prophylaxis of fibrotic diseases.


Iodine-Promoted N-H/α,β-C(sp3)-Trifunctionalization of l-Proline: Access to 3,4-Dihydrobenzo[ b][1,7]naphthyridines via Consecutive Decarboxylation/Ring Opening/Dicyclization.
A N-H/α,β-C(sp3)-trifunctionalization of l-proline, proceeding through an iodine-promoted consecutive decarboxylation/ring-opening/dicyclization process, is achieved. This strategy affords structurally diverse fused N-heterocycles in good yields with a wide substrate scope. Preliminary mechanistic studies indicate that catabolism of l-proline might be involved in this cascade reaction and the in situ generated intermediate 4-aminobutanal was identified as the key intermediate. Notably, this domino strategy enriches the reactivity of versatile l-proline in the synthesis of fused heterocycles.


Effects of dietary supplementation of bacteriophages against enterotoxigenic Escherichia coli (ETEC) K88 on clinical symptoms of post-weaning pigs challenged with the ETEC pathogen.
The present study was performed to investigate the effects of dietary supplementation of bacteriophages (phages) against enterotoxigenic Escherichia coli (ETEC) K88 as a therapy against the ETEC infection in post-weaning pigs. Two groups of post-weaning pigs aged 35 days, eight animals per group, were challenged with 3.0 × 1010 colony forming units of ETEC K88, a third group given the vehicle. The unchallenged group and one challenged group were fed a basal nursery diet for 14 days while the remaining challenged group was fed the basal diet supplemented with 1.0 × 107 plaque forming units of the phage per kg. Average daily gain (ADG), goblet cell density and villous height:crypt depth (VH:CD) ratio in the intestine were less in the challenged group than in the unchallenged group within the animals fed the basal diet (p < 0.05); the reverse was true for rectal temperature, faecal consistency score (FCS), E. coli adhesion score (EAS) in the intestine, serum interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α) concentrations and digesta pH in the stomach, caecum and colon. The ETEC infection symptom within the challenged animals was alleviated by the dietary phage supplementation (p < 0.05) in ADG, FCS, EAS in the jejunum, serum TNF-α concentration, digesta pH in the colon, goblet cell density in the ileum and colon and VH:CD ratio in the ileum. Moreover, the infection symptom tended to be alleviated (p < 0.10) by the phage supplementation in rectal temperature, EAS in the ileum and caecum, and VH:CD ratio in the duodenum and jejunum. However, EAS in the colon, digesta pH in the stomach and caecum, and goblet cell density in the jejunum did not change due to the dietary phage. Overall, results indicate that the phage therapy is effective for alleviation of acute ETEC K88 infection in post-weaning pigs.


Characteristics of the association between prothrombin fragment 2 and alpha-thrombin.
The esterolytic activity of bovine alpha-thrombin on the synthetic substrate N-alpha-p-tosyl-L-arninine methyl ester (TosArgOMe) is stimulated when the prothrombin activation fragment, prothrombin fragment 2, is added as previously reported by this laboratory (Heldebrant, C. M., and Mann, K. G. (1973), J. Biol. Chem. 248, 3642). A similar stimulation of beta-thrombin is observed upon addition of prothrombin fragment 2. The binding constant of prothrombin fragment 2 to alpha-thrombin has been determined by the method of Gutfreund ((1972), Enzymes, Physical Principles, Wiley, New York, N.Y., pp 67-71). The dissociation constant is 7.7 X 10(-10)M, and there is one molecule of prothrombin fragment 2 bound per molecule of alpha-thrombin. Prethrombin-2 competes for prothrombin fragment 2, so the enhancement of the esterolytic activity of alpha-thrombin by prothrombin fragment 2 was used as a probe to determine the dissociation constant for the binding of prothrombin fragment 2 to prethrombin 2. The dissociation constant for this association is 1.3 X 10(-10)M. The kinetic parameters for the reaction of alpha-thrombin on TosArgOMe were determined in the absence and presence of prothrombin fragment 2 and are as follows: (a) in the absence of prothrombin fragment 2, Km(app) = 1.92 X 10(-4)M, and k3(app) = 35.8 mol of TosArgOMe/mol of alpha-thrombin s(-1); (b) in the presence of prothrombin fragment 2,Km(app = 1.76 X 10(-4)M, and k3(app) = 60.5 mol of TosArgOMe/mol of alpha-thrombin s(-1). Thus, the stimulatory effect of bovine prothrombin fragment 2 on bovine alpha-thrombin is reflected in k3(app) and not in Km(app). In contrast to the stimulatory effect of prothrombin fragment 2 on the thrombin-catalyzed hydrolysis of TosArgOMe, it inhibits the activity of alpha-thrombin toward N-alpha-benzoyl-L-arginine ethyl ester and N-alpha-benzoyl-L-arginine p-nitroanilide. The inhibition of activity toward these substrates by prothrombin fragment 2 is also reflected in k3(app). Activity toward the nonspecific substrate p-nitrophenyl butyrate was completely inhibited by the addition of prothrombin fragment 2. Prothrombin fragment 2 has no effect on the inhibition of alpha-thrombin activity by the active-site serine inhibitors diisopropyl phosphofluoridate, phenylmethanesulfonyl fluoride, or p-nitrophenyl guanidinobenzoate. Inhibition by the active-site-histidine-modifying inhibitor, N-alpha-p-tosyl-L-arginine chloromethyl ketone, was enhanced by the addition of prothrombin fragment 2. Soybean trypsin inhibitor reduces the stimulation by prothrombin fragment 2, but only at high molar ratios. Prothrombin fragment 2 has no effect on the clotting activity of alpha-thrombin, nor inhibition of this activity by heparin, hirudin, or diisopropyl phosphafluoridate. Bovine prothrombin fragment 2 enhances the esterolytic activity of both human and bovine alpha-thrombin, but human prothrombin fragment 2 does not enhance the esterolytic activity of either human or bovine alpha-thrombin.


Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells.
Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient-specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation.


Fabrication of an Anti-Biofouling Plasma-Filtration Membrane by an Electrospinning Process Using Photo-Cross-linkable Zwitterionic Phospholipid Polymers.
The goal of this study is to fabricate a stable plasma filtration membrane with antibiofouling properties via an electrospinning process. To this end, a random-type copolymer consisting of zwitterionic phosphorylcholine (PC) groups and ultraviolet (UV)-cross-linkable phenyl azide groups was synthesized. The zwitterionic PC group provides antibiofouling properties, and the phenyl azide group enables the stable maintenance of the fibrous nanostructure of hydrophilic zwitterion polymers in aqueous medium via a simple UV curing process. To demonstrate the antibiofouling nature of the PC group, a polymer without antibiofouling PC groups was also prepared for comparison. The successful synthesis of the random-type copolymers containing phenyl azide groups was proven by 1H nuclear magnetic resonance and Fourier transform infrared spectroscopy, and the fibrous structure of the prepared membranes was observed by field emission scanning electron microscopy. The antibiofouling properties were analyzed by fluorescein isothiocyanate-labeled bovine serum albumin adsorption and platelet adhesion tests. The experimental results show that membranes containing zwitterionic PC groups exhibited obvious decreases in platelet adhesion and protein adsorption. Platelet-rich plasma solution was filtered using the prepared membranes to test their filtration properties. The sequential filtration process removed 80% and almost 98% of the platelets. This finding confirmed that the membrane retained its blood-inert biomaterial surface in a complex medium that included blood plasma and platelets.


Knowledge and beliefs on cervical cancer and practices on cervical cancer screening among women aged 20 to 50 years in Ouagadougou, Burkina Faso, 2012: a cross-sectional study.
In Burkina Faso, 1230 women are diagnosed with cervical cancer every year and 838 die from the disease. Little is known about women's practices, knowledge and beliefs regarding cervical cancer. This study aims to describe women's practices regarding cervical cancer screening and to assess their knowledge and beliefs. Cross-sectional study was carried out in Ouagadougou from 1st to 31st December 2012 interviewing 840 women aged 20 to 50 years about their knowledge, beliefs and practices regarding cervical cancer. Cluster sampling was used. Univariate and multivariate logistic regression analysis were performed. Chi square test was used and p-value < 0.05 was considered. Out of 840 women enrolled with mean age 29.5 ± 7.77 years, 66.31% were married, 59.28% have not been to school or left school at primary level. While 64.2% of participants heart about cervical cancer, 8.5% heart about Human papillomavirus, 69.05% don't know that cervical cancer is preventable. 90.4% of participants were worried to develop cervical cancer, 96.67% would accept to be screened and 11.07% were screened for cervical cancer. In multivariate analysis, heart about cervical cancer (OR = 5.7; 95% CI: 2.21-14.69), know contamination mode of HPV (OR = 3.81; 95% CI: 2.27-6.39), heart about HPV (OR = 2.05; 95% CI: 1.11-3.81) and use of oral contraceptive (OR = 2.06; 95% CI: 1.25-3.39) were independently associated with screening history with p < 0.05. Knowledge and belief regarding cervical cancer is limited among Ouagadougou women and screening rate is low. There is need to enhance health education regarding Human papillomavirus and cervical cancer.


Hippocampal spatial position evaluation on MRI for research and clinical practice.
In clinical practice as well as in many volumetric studies we use different reorientations of the brain position towards x and y axis on the magnetic resonance imaging (MRI) scans. In order to find out whether it has an overall effect on the resulting 2D data, manual hippocampal area measurements and rotation variability of the brain (in two reoriented axes) and the skull were performed in 23 Alzheimer's disease patients and 31 healthy controls. After the MRI scanning, native brain scans (nat) were reoriented into the two different artificial planes (anterior commissure-posterior commissure axis (AC-PC) and hippocampal horizontal long axis (hipp)). Hippocampal area and temporal horn of the lateral ventricle was measured manually using freeware Image J program. We found that 1) hippocampal area of nat images is larger compared to hipp images, area of the nat images is equal to the AC-PC images and area of the hipp images is smaller compared to AC-PC images, 2) hippocampal area together with the area of the temporal horn for nat images is larger compared to hipp images, area of the hipp images is smaller compared to the AC-PC images and area of the nat images is smaller compared to the AC-PC images. The conclusion is that the measured area of the hippocampus in the native MRI is almost the same as the area of MRI reoriented only into the AC-PC axis. Therefore, when performing 2D area studies of the hippocampus or in the clinical practice we recommend usage of not-reoriented MRI images or to reorient them into the AC-PC axis. Surprising finding was that rotation of both AC-PC and hipp line towards x-axis among patients varies up to 35° and the same is true for the skull rotation so that it is not only a matter of the brain position.


Management of craniopharyngiomas in children.
Craniopharyngiomas are histologically benign neoplasms occurring in the intra- and suprasellar region. Their location and close relation with visual pathways, hypothalamus and major basal vessels may cause difficulty in resecting these tumors without surgical complications. Radiotherapy after limited resection of craniopharyngiomas has been advocated by some investigators while others contend radical resections by means of advanced surgical techniques afford better outcome of patients. Although optimal treatment is yet to be defined, the review of our institutional experience and the critical analysis of the literature show that radiation therapy may be effective but not curative. It is recommended that surgeons should make every effort to effect total excision at the initial operation.


Pacemaker malfunction following transthoracic countershock.
Electrical cardioversion or defibrillation may be necessary in patients with implanted artificial cardiac pacemakers. Sudden discharge of high electrical energy employed in DC transthoracic countershock procedures may damage the sensitive pacemaker circuitry and result in malfunction. We report a case in which, following synchronized DC countershock, a non-programmable demand pacemaker functioned in the R-wave triggered mode rather than the R-wave inhibited mode as designed. Further, the pacemaker output voltage was reduced to about half its specified output. Such a malfunction may not be readily apparent, and requires careful analysis following electric shock.


Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.


Prediction of non-muscle invasive bladder cancer outcomes assessed by innovative multimarker prognostic models.
We adapted Bayesian statistical learning strategies to the prognosis field to investigate if genome-wide common SNP improve the prediction ability of clinico-pathological prognosticators and applied it to non-muscle invasive bladder cancer (NMIBC) patients. Adapted Bayesian sequential threshold models in combination with LASSO were applied to consider the time-to-event and the censoring nature of data. We studied 822 NMIBC patients followed-up >10 years. The study outcomes were time-to-first-recurrence and time-to-progression. The predictive ability of the models including up to 171,304 SNP and/or 6 clinico-pathological prognosticators was evaluated using AUC-ROC and determination coefficient. Clinico-pathological prognosticators explained a larger proportion of the time-to-first-recurrence (3.1 %) and time-to-progression (5.4 %) phenotypic variances than SNPs (1 and 0.01 %, respectively). Adding SNPs to the clinico-pathological-parameters model slightly improved the prediction of time-to-first-recurrence (up to 4 %). The prediction of time-to-progression using both clinico-pathological prognosticators and SNP did not improve. Heritability (ĥ (2)) of both outcomes was <1 % in NMIBC. We adapted a Bayesian statistical learning method to deal with a large number of parameters in prognostic studies. Common SNPs showed a limited role in predicting NMIBC outcomes yielding a very low heritability for both outcomes. We report for the first time a heritability estimate for a disease outcome. Our method can be extended to other disease models.


Temporal relationship between trunk and thigh contributes to balance control in load carriage walking.
Load carriage walking (LCW) challenges a person's balance as the load increases their forward trunk inclination, shifting the center of mass (COM) forward with respect to the base of support (BOS). We examined LCW to understand whether and how healthy people adjust the temporal relationship (TR) between the trunk and leg for balance control. Ten subjects were recruited to perform unloaded walking and LCW. The TR between the trunk and leg was measured by the continuous relative phase. The maximum forward displacement of the COM with respective to the BOS (FDCOM(BOS)) was recorded during the stance phase. We found that the TR was shifted in LCW, and the shift was associated with a decrease in the maximum FDCOM(BOS). The findings suggest that the TR between the trunk and leg contributes to balance control, and it may be a variable that needs to be addressed in gait rehabilitation.


[Comments on the interpretation of the term "medical devices"].
The Court of Justice of the European Union made a decision on medical devices as non-medicinal products for intended use in interpreting the concept of free movement of goods, such as operating principles concerning the subject matter of the interpretation of Directive 93/42/ EEC - in preliminary ruling according to article 267 of TFEU - on 22 November 2012. With its decision, given assigned explained the concept of the scope of medical devices. The decision of the Court is binding not only for the national court initiating a request for the preliminary ruling, but also for all courts of the Member States. Official reference: Dated judgement 22 November 2012 of the Court of Justice of the European Union to C-219/ Case no. 11 - in preliminary ruling according to article 267 of TFEU. Interpreted provisions: Directive 2007/47/EC of The European Parliament and of the Council of 5 September 2007 as amended by the Council Directive 93/42/EEC of 14 June 1993 concerning medical devices 1st (2) a) first, second and third indent.


Non-codon Optimized PiggyBac Transposase Induces Developmental Brain Aberrations: A Call for in vivo Analysis.
In this perspective article, we briefly review tools for stable gain-of-function expression to explore key fate determinants in embryonic brain development. As the piggyBac transposon system has the highest insert size, a seamless integration of the transposed sequence into the host genome, and can be delivered by transfection avoiding viral vectors causing an immune response, we explored its use in the murine developing forebrain. The original piggyBac transposase PBase or the mouse codon-optimized version mPB and the construct to insert, contained in the piggyBac transposon, were introduced by in utero electroporation at embryonic day 13 into radial glia, the neural stem cells, in the developing dorsal telencephalon, and analyzed 3 or 5 days later. When using PBase, we observed an increase in basal progenitor cells, often accompanied by folding aberrations. These effects were considerably ameliorated when using the piggyBac plasmid together with mPB. While size and strength of the electroporated region was not correlated to the aberrations, integration was essential and the positive correlation to the insert size implicates the frequency of transposition as a possible mechanism. We discuss this in light of the increase in transposing endogenous viral vectors during mammalian phylogeny and their role in neurogenesis and radial glial cells. Most importantly, we aim to alert the users of this system to the phenotypes caused by non-codon optimized PBase application in vivo.


Cell death signalling pathways in the pathogenesis and therapy of haematologic malignancies: overview of apoptotic pathways.
Apoptosis, a Greek descriptive term for falling leaves or petals, plays an important role in the progression of many diseases. Apoptosis is essential for the development and survival of multi-cellular organisms. Malignant diseases, including haematologic malignancies, are associated with defects in the cell death mechanism. These defects are not only important for the growth advantage of malignant clones, but when understood can be used for specific therapeutic targeting of malignant cells while sparing normal cells. The cellular and molecular mechanisms of apoptosis have been extensively demonstrated and are reviewed in this article. In this part of the review we focus on basic details of the apoptosis pathways, key players of the receptor-mediated apoptosis, and molecules involved in the cross-talk between individual apoptosis pathways and apoptosis regulation.


Single-crystalline silver films for plasmonics.
A simple route to flat, large-area, single-crystalline films for plasmonics is demonstrated by sputter deposition of silver onto mica substrates at elevated temperatures. The films exhibit improved dielectric properties and allow more precise patterning of high-quality nanostructures for plasmonic applications.


Direct Binding and Regulation by Fur and HapR of the Intermediate Regulator and Virulence Factor Genes Within the ToxR Virulence Regulon in Vibrio cholerae.
Cholera toxin (CT) and toxin coregulated pilus (TCP, TcpA is the major subunit) are two major virulence factors of Vibrio cholerae, both of which play critical roles in developing severe diarrhea in human. Expression of CT and TCP is under the tight control of the regulatory cascade known as the ToxR virulence regulon, which is composed of three regulators ToxR, TcpP, and ToxT. Besides, their expression is also regulated by the quorum sensing (QS) master regulator HapR and the regulatory protein Fur. Though transcription of tcpP, toxT, and/or tcpA are reported to be regulated by HapR and Fur, to date there are no studies to verify their direct regulations. In the present study, we showed that HapR directly repress the transcription of tcpP and tcpA by binding to their promoter regions, and possibly repress toxT transcription in an indirect manner. Fur directly activated the transcription of tcpP, toxT, and tcpA by binding to their promoters. Taking account of the sequential expression of hapR, fur, tcpP, toxT, and tcpA in the different growth phases of V. cholerae, we deduce that at the early mid-logarithmic growth phase, Fur binds to the promoters of tcpP, toxT, and tcpA to activate their transcription; while at the later mid-logarithmic growth phase, HapR can bind to the promoters of tcpP and tcpA to repress their transcription. Our study reveals the new recognition in the virulence regulatory pathways in V. cholerae and suggests the complicated and subtle regulation network with the growth density dependence.


[Molecular targeted therapies for metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors].
This review addresses molecular targeted therapies for metastatic breast cancer. As the complex cellular aberrations inherent to cancer cells continue to be revealed, new therapies to target specific cellular pathways are being developed, and several are currently in clinical trials. The most promising of these new agents are discussed focusing on monoclonal antibodies and tyrosine kinase inhibitors to human epidermal growth factor receptors (HER) and vascular endothelial growth factor (VEGF).


Integration of multiple memories in sensory preconditioning.
The present study demonstrates that humans' response to a single stimulus (S1) is determined by what follows S1's associates. The experiment used a sensory preconditioning (SPC) design where S1 was associated with both S2 and S3 on separate trials before establishing relationships between these latter stimuli with an outcome or its absence in a second phase. When S2 and S3 were associated with the same consequence, either an outcome or its absence, strong consequence-based responding to S1 was observed in a reaction time test. Participants responded quickly to indicate that the outcome was, or was not, predicted by S1. When S2 predicted the outcome and S3 did not, SPC was weaker although participants were not slower to respond to S1. Implications on the understanding of the mechanisms that allow for the response to S1 to emerge are discussed.


Radicals in Biology: Your Life Is in Their Hands.
Radicals in biology, once thought to all be bad actors, are now known to play a central role in many enzymatic reactions. Of the known radical-based enzymes, ribonucleotide reductases (RNRs) are pre-eminent as they are essential in the biology of all organisms by providing the building blocks and controlling the fidelity of DNA replication and repair. Intense examination of RNRs has led to the development of new tools and a guiding framework for the study of radicals in biology, pointing the way to future frontiers in radical enzymology.


[Evidence for metabolites of the cornea (author's transl)].
The supply of nutrient metabolites to the cornea is largely dependent on the levels of aqueous humour metabolites. When the ciliary body was destroyed totally by cyclodiathermy, a deficiency of glucose was observed in the aqueous humor and consequently in the corneal stroma. The diminished glucose levels could be increased by intravenous glucose infusions to values above normal. On the other hand, fructose infusions may be of value as nutrient metabolites of the cornea. Analyses of the fructose levels in the anterior segment of the eye showed that significant quantities of fructose were present in the corneal epithelium with a concentration gradient to the stroma and the aqueous humor. When the corneal epithelium was removed, the fructose of the corneal stroma and the aqueous humor was significantly diminished. In aphakic eyes without corneal epithelium, the fructose levels were decreased to nearly zero values both in the corneal stroma and in the aqueous humor. It was concluded that corneal epithelium was able to synthesize fructose and release it into the aqueous humor.