Prevalence and severity of differing dimensions of breathlessness among elderly males in the population.
Breathlessness is common in the general population. Existing data were obtained primarily with the uni-dimensional modified Medical Research Council breathlessness scale (mMRC) that does not assess intensities of unpleasantness nor physical, emotional and affective dimensions. The aim of this research was to determine the prevalence and intensity of these dimensions of breathlessness in elderly males and any associations with their duration, change over time and mMRC grade. We conducted a population-based, cross-sectional study of 73-year-old males in a county in southern Sweden. Breathlessness was self-reported at one time point using a postal survey including the Dyspnea-12 (D-12), the Multidimensional Dyspnea Profile (MDP) and the mMRC. Presence of an increased dimension score was defined as a score ≥minimal clinically important difference for each dimension scale. Association with the mMRC, recalled change since age 65, and duration of breathlessness were analysed with linear regression. Among 907 men, an increased dimension score was present in 17% (D-12 total score), 33% (MDP A1 unpleasantness), 19% (D-12 physical), 17% (MDP immediate perception), 10% (D-12 affective) and 17% (MDP emotional response). The unpleasantness and affective dimensions were strongly associated with mMRC≥3. Higher MDP and D-12 scores were associated with worsening of breathlessness since age 65, and higher MDP A1 unpleasantness was associated with breathlessness of less than 1 year duration. Increased scores of several dimensions of breathlessness are prevalent in 73-year-old males and are positively correlated with mMRC scores, worsening of breathlessness after age 65, and duration of less than 1 year.


Rising inequality and the implications for the future of private insurance in Canada.
Income and wealth inequality have risen in Canada since its low point in the 1980s. Over that same period we have also seen an increase in the amount that Canadians spend on privately financed health care, both directly and through private health insurance. This paper will explore the relationship between these two trends using both comparative data across jurisdictions and household-level data within Canada. The starting hypothesis is that the greater the level of inequality the more difficult it becomes for publicly provided insurance to satisfy the median voter. Thus, we should expect increased pressure to access privately financed alternatives as inequality increases. In the light of these implications, the paper considers the implications for the future of private insurance in Canada.


Notch2 is required for formation of the placental circulatory system, but not for cell-type specification in the developing mouse placenta.
We have previously reported that a mutation in the ankyrin repeats of mouse Notch2 results in embryonic lethality by embryonic day 11.5 (E11.5), showing developmental retardation at E10.5. This indicated that Notch2 plays an essential role in postimplantation development in mice. Here, we demonstrate that whole embryo culture can circumvent developmental retardation of Notch2 mutant embryos for up to 1 day, suggesting that the lethality was primarily caused by extraembryonic defects. Histological examinations revealed delayed entry of maternal blood into the mutant placenta and poor blood sinus formation at later stages. Notch2-expressing cells appeared around maternal blood sinuses. Specification of trophoblast subtypes appeared not to be drastically disturbed and expression of presumptive downstream genes of Notch2 signaling was not altered by the Notch2 mutation. Thus, in the developing mouse placenta, Notch2 is unlikely to be involved in cell fate decisions, but rather participates in formation of maternal blood sinuses. In aggregation chimeras with wild-type tetraploid embryos, the mutant embryos developed normally until E12.5, but died before E13.5. The chimeric placentas showed a restored maternal blood sinus formation when compared with the mutant placentas, but not at the level of wild-type diploid placentas. Therefore, it was concluded that the mutant suffers from defects in maternal blood sinus formation. Thus, Notch2 is not cell autonomously required for the early cell fate determination of subtypes of trophoblast cells, but plays an indispensable role in the formation of maternal blood sinuses in the developing mouse placenta.


Ultrafast thin-disk laser with 80 μJ pulse energy and 242 W of average power.
We present a semiconductor saturable absorber mirror (SESAM) mode-locked thin-disk laser generating 80 μJ of pulse energy without additional amplification. This laser oscillator operates at a repetition rate of 3.03 MHz and delivers up to 242 W of average output power with a pulse duration of 1.07 ps, resulting in an output peak power of 66 MW. In order to minimize the parasitic nonlinearity of the air inside the laser cavity, the oscillator was operated in a vacuum environment. To start and stabilize soliton mode locking, we used an optimized high-damage threshold, low-loss SESAM. With this new milestone result, we have successfully scaled the pulse energy of ultrafast laser oscillators to a new performance regime and can predict that pulse energies of several hundreds of microjoules will become possible in the near future. Such lasers are interesting for both industrial and scientific applications, for example for precise micromachining and attosecond science.


Determinants and assessment of regurgitation after mitral valve repair.
The ability to detect residual regurgitation is important in the management of patients after mitral valve repair. We performed a study of 264 patients to determine the risk factors and to compare the accuracy of clinical assessment with that of echocardiography. Operative details and valve pathologic data were obtained from individual patient case notes. Clinical assessment consisted of history, examination, and electrocardiography. The presence of regurgitation was ranked in 7 grades, from none to severe. Transthoracic echocardiography was performed blinded to and independently of clinical assessment on the same visit and was graded similarly. Univariate analyses of demographic, etiologic, and operative variables were performed. Significant factors were entered into a multivariate logistic regression model. Sensitivities and specificities were calculated for each diagnostic modality, and the kappa statistic was used to express agreement. Mean (+/- SE) freedoms from regurgitation at 1 and 5 years were 91.5% +/- 1.7% and 47.5% +/- 3.2%. Factors independently associated with postoperative regurgitation were poor ventricular function (P =.04), increased age (P =.01), and chordal procedures (P =.006). When assessing the presence of regurgitation, auscultation conferred a specificity of 78%, a sensitivity of 77%, and a kappa of 0.43 relative to echocardiography. Electrocardiographic criteria for left ventricular hypertrophy were superior, with a complete specificity of 100% but a low sensitivity of 15%. Agreement within 7 grades of severity was moderate, with a weighted kappa value of 0.42. The hazard function for regurgitation after mitral repair increases steadily after the third year, with ventricular function, age and chordal procedures as independent risks. Clinical assessment and electrocardiography are excellent in identifying regurgitation, but their agreement is less when grading severity.


Factors affecting the distribution of cytoplasmic incompatibility in Drosophila simulans.
In Drosophila simulans a Wolbachia-like microorganism is responsible for reduced egg-hatch when infected males mate with uninfected females. Both incompatibility types have previously been found in North America, Europe and Africa. Some California populations have remained polymorphic for over two years, and the infection is apparently spreading in central California. Egg hatch proportions for wild-caught females from polymorphic populations show that the incompatibility system acts in nature, but egg mortality rates are apparently lower than observed in laboratory populations. Although infected females maintained under various laboratory conditions never produce uninfected offspring, some wild-caught infected females produce both infected and uninfected progeny. This helps explain the persistence of a low frequency of uninfected flies in predominantly infected populations and may also explain the other polymorphisms observed. Fitness comparisons of infected and uninfected stocks, including both larval and adult fitness components, indicate that fecundity may be the component most affected. Infected females suffer a fecundity reduction of 10-20% in the laboratory, but the reduction seems to be smaller in nature. A theoretical analysis provides some insight into the population biology of the infection.


Impact of host community composition on Lyme disease risk.
The drivers of variable disease risk in complex multi-host disease systems have proved very difficult to identify. Here we test a model that explains the entomological risk of Lyme disease (LD) in terms of host community composition. The model was parameterized in a continuous forest tract at the Cary Institute of Ecosystem Studies (formerly the Institute of Ecosystem Studies) in New York State, U.S.A. We report the results of continuing longitudinal observations (10 years) at the Cary Institute, and of a shorter-term study conducted in forest fragments in LD endemic areas of Connecticut, New Jersey, and New York, USA. Model predictions were significantly correlated with the observed nymphal infection prevalence (NIP) in both studies, although the relationship was stronger in the longer-term Cary Institute study. Species richness was negatively, albeit weakly, correlated with NIP (logistic regression), and there was no relationship between the Shannon diversity index (H') and NIP. Although these results suggest that LD risk is in fact dependent on host diversity, the relationship relies explicitly on the identities and frequencies of host species such that conventional uses of the term biodiversity (i.e., richness, evenness, H') are less appropriate than are metrics that include species identity. This underscores the importance of constructing interaction webs for vertebrates and exploring the direct and indirect effects of anthropogenic stressors on host community composition.


National physical education curriculum: motor and cardiovascular health related fitness in Greek adolescents.
State school physical education (PE) programmes are common throughout Greece. However, it is not known if the main objectives of the Greek PE curriculum are achieved. To assess the current national PE curriculum in relation to selected motor and cardiovascular health related fitness parameters. A sample of 84 Greek schoolboys (mean (SD) age 13.6 (0.3) years, height 160.7 (8.6) cm, weight 50 (10.8) kg) volunteered. Forty three indicated participation only in school PE classes and habitual free play (PE group). The remaining 41 were involved in extracurricular organised physical activities in addition to school PE and habitual free play (PE+ group). The subjects underwent anthropometric, motor (flexibility, balance, standing broad jump, hand grip, sit ups, and plate tapping), and cardiovascular health related (percentage body fat, aerobic fitness, and physical activity) fitness assessments. Children in the PE group had inferior motor and cardiovascular health related fitness profiles compared with those in the PE+ group. Body fat (20.3 (8.8) v 13.9 (3.5); p<0.001), aerobic fitness (34.7 (3.7) v 43.9 (4.2); p<0.001), and time spent in intensive physical activity (0.2 (0.2) v 0.7 (0.3); p<0.001) showed the greatest differences between the two groups. In the pupils in the PE group, these were lower than the levels proposed to be necessary to combat future health risks. Adjustments for confounding variables showed a decrease in the significance of motor fitness, but not in cardiovascular health related parameters. The national PE curriculum for Greek secondary schools does not achieve the required levels of motor and cardiovascular health related fitness and should be reconsidered.


A 15 amino acid fragment of influenza nucleoprotein synthesized in the cytoplasm is presented to class I-restricted cytotoxic T lymphocytes.
A recombinant vaccinia has been designed to express amino acids 366-379 of influenza nucleoprotein, previously shown to be the minimal epitope recognized by a class I-restricted cytotoxic T cell clone. Target cells infected with the recombinant vaccinia virus expressing this peptide are recognized by CTL as efficiently as target cells expressing the complete nucleoprotein. The results imply the existence of a peptide transport system that constitutively passes the products of degraded proteins from the cytoplasm into a membrane-bound compartment of the cell.


Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study.
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4-48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8-46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3-67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2-30·2) of 16 patients with gastric cancer, four (25%, 7·3-52·4) of 16 patients with urothelial cancer, and five (39%, 13·9-68·4) of 13 patients with endometrial cancer. Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. Synthon Biopharmaceuticals.


Tunable Microscale Porous Systems with Dynamic Liquid Interfaces.
Solid microscale porous material systems have attracted more attention in recent years due to their various potential applications, such as energy source transportations, biomedical devices, wastewater treatments, phase separations, etc. However, such systems are still plagued with many issues including fouling, mechanical fragility, inability to self-heal, and low recyclability that restrict them for further industrial applications. Dynamic liquid-based microscale porous material systems, especially porous surfaces and membranes, provide a new opportunity for resolving these issues and possess many benefits, such as antifouling, slippery, transparent, recovery, self-healing, and recycling properties. This Concept is mainly concerned with how to obtain tunable microscale porous systems with dynamic liquid interfaces, and their applications from the surfaces to membranes. The authors hope this concept will attract interest of scientists in areas related to the rapid development and application of various liquid-based porous systems.


SUMO Safeguards Somatic and Pluripotent Cell Identities by Enforcing Distinct Chromatin States.
Understanding general principles that safeguard cellular identity should reveal critical insights into common mechanisms underlying specification of varied cell types. Here, we show that SUMO modification acts to stabilize cell fate in a variety of contexts. Hyposumoylation enhances pluripotency reprogramming in vitro and in vivo, increases lineage transdifferentiation, and facilitates leukemic cell differentiation. Suppressing sumoylation in embryonic stem cells (ESCs) promotes their conversion into 2-cell-embryo-like (2C-like) cells. During reprogramming to pluripotency, SUMO functions on fibroblastic enhancers to retain somatic transcription factors together with Oct4, Sox2, and Klf4, thus impeding somatic enhancer inactivation. In contrast, in ESCs, SUMO functions on heterochromatin to silence the 2C program, maintaining both proper H3K9me3 levels genome-wide and repression of the Dux locus by triggering recruitment of the sumoylated PRC1.6 and Kap/Setdb1 repressive complexes. Together, these studies show that SUMO acts on chromatin as a glue to stabilize key determinants of somatic and pluripotent states.


Fate of the HA coating of loaded implants in the augmented sinus floor: a human case study of retrieved implants.
A histomorphometric study was performed on six retrieved loaded hydroxyapatite (HA)-coated titanium implants. The implants had been clinically functioning in a 50-year-old patient. She originally presented a severely atrophic maxilla that was reconstructed by sinus floor augmentation using autogenous bone from the iliac crest. In spite of good clinical function, because of psychiatric problems, all implants, including some bordering bone, were removed using a trephine bur. Thin ground sections were prepared for histology and used for histomorphometry. The aim of this study was to observe the condition of the calcium phosphate coating after 2.5 years of functional loading, the nature of the bone-to-implant interface, as well as the density of the bone graft around the implants. Intimate and abundant bone-to-implant contact was observed, ranging from 90.4% to 99.8% along the implant surface. Active bone remodeling occurred within all threads, as demonstrated by secondary osteons close to the implant surface. The thickness of the calcium phosphate coating varied from 51 to 88 pm for the loaded retrieved implants, versus 53 to 89 microm for the nonused control implant. All implants showed bone contact including the first thread and up to the smooth titanium neck. Both the nature and thickness of the coating had hardly changed after 2.5 years of loading. The HA-coated implants used achieved excellent osseointegration and must be considered clinically safe and effective in maxillary grafted bone.


Obesity and eating behaviour in children and adolescents: contribution of common gene polymorphisms.
The prevalence of childhood obesity is increasing in many countries and confers risks for early type 2 diabetes, cardiovascular disease and metabolic syndrome. In the presence of potent 'obesogenic' environments not all children become obese, indicating the presence of susceptibility and resistance. Taking an energy balance approach, susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. Evidence shows that heritability estimates for BMI and body fat are paralleled by similar coefficients for energy intake and preferences for dietary fat. Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and the phenotypic response involves overconsumption and a failure to inhibit eating. Investigations of robustly characterized common gene variants of fat mass and obesity associated (FTO), peroxisome proliferator-activated receptor (PPARG) and melanocortin 4 receptor (MC4R) which contribute to variance in BMI also influence the variance in appetite factors such as measured energy intake, satiety responsiveness and the intake of palatable energy-dense food. A review of the evidence suggests that susceptibility to childhood obesity involving specific allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in activity-related energy expenditure. This conclusion has implications for early detection of susceptibility, and for prevention and management of childhood obesity.


Juveniles adjudicated incompetent to proceed: a descriptive study of Florida's Competence Restoration program.
Although competence to stand trial is perhaps the most studied area of mental health law, most of the research has been focused on adults. This study describes a population of 471 juveniles committed for treatment/habilitation and restoration of their competence to proceed in the delinquency process. This population differed from their adult counterparts in important ways. For example, 58 percent of the juveniles had a diagnosis of mental retardation, and 57 percent of the juveniles with an Axis I diagnosis also had a diagnosis of conduct disorder. Only 17 percent had a diagnosed psychotic disorder. Diagnoses among cohorts of adults found incompetent differ markedly. However, similar to adult defendants who are adjudicated incompetent to proceed, the majority of these children were returned to court after treatment staff determined that they were competent to proceed. Contrary to expectation, there were no significant age-related differences with respect to the recommendation of clinical staff regarding restoration of competence. The data suggest the need for further research examining that subset of children in the juvenile justice system whose competence to proceed is questionable.


Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.
Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.


Neurohormonal activation in patients with mild or moderately severe congestive heart failure and effects of ramipril. The Ramipril Trial Study Group.
To describe neurohormonal activation in patients with mild or moderate heart failure and how it may be modified by treatment with ramipril. Cardiology departments at 24 hospitals in Denmark, Finland, Norway, and Sweden. 223 patients with mild or moderately severe congestive heart failure who were taking diuretics with or without digitalis. Randomised, double bind, multicentre, placebo controlled comparison of ramipril and placebo. Venous blood samples were drawn at rest, before blind treatment, and after 12 weeks of treatment with the study drug. A probability prediction score for mortality derived by stepwise linear discriminant from neurohormone data in the first cooperative north Scandinavian enalapril survival study (CONSENSUS I) was used to assess combined activity of the different neurohormonal systems. Plasma concentrations of atrial natriuretic peptide were raised at baseline but angiotensin II, aldosterone, and noradrenaline concentrations were within normal limits. There was, however, a wide interindividual variation. Plasma noradrenaline concentration and prediction score were higher among patients with class III congestive heart failure according to the New York Heart Association's classification than among patients with class II congestive heart failure (P < 0.05). There was a modest but significant inverse correlation between exercise duration at baseline and plasma noradrenaline concentration (r = -0.21, P = 0.0023), aldosterone concentration (r = -0.14, P = 0.04), and prediction score (r = -0.24, P = 0.0004). Prediction score at baseline was significantly higher among those who died (n = 10) than among survivors (P = 0.03). Angiotensin converting enzyme activity was suppressed and plasma concentrations of aldosterone and atrial natriuretic peptide were reduced after 12 weeks of treatment with ramipril compared with placebo. In patients with the most pronounced neurohormonal activation at baseline (highest third of noradrenaline concentration or prediction score), noradrenaline concentration and prediction score were significantly lower after 12 weeks of taking ramipril compared with placebo. Patients with a prediction score in the highest third at baseline had a higher heart rate than to those in the lowest third (P = 0.003). Neurohormonal activation is associated with the degree of symptoms and the severity of disease in mild or moderately severe congestive heart failure. Treatment with ramipril attenuates neurohormonal activation. This effect is most pronounced among patients with the highest circulating concentrations of neurohormones before the start of treatment.


Dual phospholipase C/diacylglycerol requirement for protein kinase D1 activation in lymphocytes.
The serine/threonine kinase protein kinase D1 (PKD1) is a protein kinase C (PKC) substrate that mediates antigen receptor signal transduction in lymphocytes. PKC phosphorylates serines 744/748 within the PKD1 catalytic domain, and this is proposed to be necessary and sufficient for enzyme activation. Hence, a PKD1 mutant with alanine substituted at positions 744 and 748 (PKD-S744A/S748A) is catalytically inactive. Conversely, a PKD1 mutant with glutamic residues substituted at positions 744 and 748 as phospho-mimics (PKD-S744E/S748E) is constitutively active when expressed in Cos7 or HeLa cells. The present study reveals that Ser-744/Ser-748 phosphorylation is required for PKD1 activation in lymphocytes. However, PKD-S744E/S748E is not constitutively active but, like the wild type enzyme, requires antigen receptor triggering or phorbol ester stimulation. Antigen receptor activation of wild type PKD is dependent on phospholipase C (PLC)/diacylglycerol (DAG) and PKC, whereas PKD-S744E/S748E is only dependent on PLC/DAG but no longer requires PKC. Hence, substitution of serines 744 and 748 with glutamic residues as phospho-mimics bypasses the PKC requirement for PKD1 activation but does not bypass the need for antigen receptors, PLC, or DAG. In lymphocytes, PKD1 is, thus, not regulated by PLC and PKC in a linear pathway; rather, PKD1 activation has more stringent requirements for integration of dual PLC signals, one mediated by PKCs and one that is PKC-independent.


Shifts of effective connectivity within a language network during rhyming and spelling.
We used functional magnetic resonance imaging to examine task-specific modulations of effective connectivity within a left-hemisphere language network during spelling and rhyming judgments on visually presented words. We identified sites showing task-specific activations for rhyming in the lateral temporal cortex (LTC) and for spelling in the intraparietal sulcus (IPS). The inferior frontal gyrus (IFG) and fusiform gyrus were engaged by both tasks. Dynamic causal modeling showed that each task preferentially strengthened modulatory influences converging on its task-specific site (LTC for rhyming, IPS for spelling). These remarkably selective and symmetrical findings demonstrate that the nature of the behavioral task dynamically shifts the locus of integration (or convergence) to the network component specialized for that task. Furthermore, they suggest that the role of the task-selective areas is to provide a differential synthesis of incoming information rather than providing differential control signals influencing the activity of other network components. Our findings also showed that switching tasks led to changes in the target area influenced by the IFG, suggesting that the IFG may play a pivotal role in setting the cognitive context for each task. We propose that task-dependent shifts in effective connectivity are likely to be mediated through top-down modulations from the IFG to the task-selective regions in a way that differentially enhances their sensitivity to incoming word-form information.


Deciphering membrane insertion of the diphtheria toxin T domain by specular neutron reflectometry and solid-state NMR spectroscopy.
Insertion and translocation of soluble proteins into and across biological membranes are involved in many physiological and pathological processes, but remain poorly understood. Here, we describe the pH-dependent membrane insertion of the diphtheria toxin T domain in lipid bilayers by specular neutron reflectometry and solid-state NMR spectroscopy. We gained unprecedented structural resolution using contrast-variation techniques that allow us to propose a sequential model of the membrane-insertion process at angstrom resolution along the perpendicular axis of the membrane. At pH 6, the native tertiary structure of the T domain unfolds, allowing its binding to the membrane. The membrane-bound state is characterized by a localization of the C-terminal hydrophobic helices within the outer third of the cis fatty acyl-chain region, and these helices are oriented predominantly parallel to the plane of the membrane. In contrast, the amphiphilic N-terminal helices remain in the buffer, above the polar headgroups due to repulsive electrostatic interactions. At pH 4, repulsive interactions vanish; the N-terminal helices penetrate the headgroup region and are oriented parallel to the plane of the membrane. The C-terminal helices penetrate deeper into the bilayer and occupy about two thirds of the acyl-chain region. These helices do not adopt a transmembrane orientation. Interestingly, the T domain induces disorder in the surrounding phospholipids and creates a continuum of water molecules spanning the membrane. We propose that this local destabilization permeabilizes the lipid bilayer and facilitates the translocation of the catalytic domain across the membrane.


Multi-Label Classification by Semi-Supervised Singular Value Decomposition.
Multi-label problems arise in various domains, including automatic multimedia data categorization, and have generated significant interest in computer vision and machine learning community. However, existing methods do not adequately address two key challenges: exploiting correlations between labels and making up for the lack of labelled data or even missing labelled data. In this paper, we proposed to use a semi-supervised singular value decomposition (SVD) to handle these two challenges. The proposed model takes advantage of the nuclear norm regularization on the SVD to effectively capture the label correlations. Meanwhile, it introduces manifold regularization on mapping to capture the intrinsic structure among data, which provides a good way to reduce the required labelled data with improving the classification performance. Furthermore, we designed an efficient algorithm to solve the proposed model based on the alternating direction method of multipliers, and thus, it can efficiently deal with large-scale data sets. Experimental results for synthetic and real-world multimedia data sets demonstrate that the proposed method can exploit the label correlations and obtain promising and better label prediction results than the state-of-the-art methods.


Access to information sources and treatment considerations among men with local stage prostate cancer.
To determine the role of information sources in the treatment decision-making process of men diagnosed with local stage prostate cancer. Diagnosed men have access to a large number of information sources about therapy, including print and broadcast media, the Internet, books, and friends with the disease. Prospective survey of men with local stage prostate cancer in 3 geographically separate regions was carried out. Most men were surveyed after diagnosis but before starting therapy. On average, men with local prostate cancer consulted nearly 5 separate sources of information before treatment. The most common source of information was the patient's physician (97%), followed by lay-literature (pamphlets, videos) (76%), other health professionals (71%), friends with prostate cancer (67%), and the Internet (58%). Most men rated the sources they consulted as helpful. Consulting the Internet was associated with considering more treatment options. Several information sources were significantly associated with considering particular treatments, but the magnitude of association was small in relation to patient age, comorbidity, and Gleason score. More than 70% of men stated that they were considering or planning only one type of therapy. Men with local stage prostate cancer consult a wide range of information sources. Nonphysician information sources appear to influence their treatment considerations, but to a smaller degree than clinical factors.


Very fast analysis of impurities in immunoglobulin concentrates using conjoint liquid chromatography on short monolithic disks.
Transferrin and albumin are often present in immunoglobulin G (IgG) concentrates and are considered as impurities. Therefore, it is important to determine their concentration in order to obtain a well-characterized biological product. Here, we describe their determination based on conjoint liquid chromatography (CLC). The established method combines two different chromatographic modes in one step: affinity and ion-exchange chromatography (IEC) combined in one column. Therefore, two CIM Protein G and one CIM quaternary amine (QA) monolithic disks were placed in series in one housing forming a CLC monolithic column. Binding conditions were optimized in a way that immunoglobulins were captured on the CIM Protein G disks, while transferrin and albumin were bound on the CIM QA disks. Subsequently, transferrin and albumin were eluted separately by a stepwise gradient with sodium chloride, whereas immunoglobulins were released from the Protein G ligands by applying low pH. A complete separation of all three proteins was achieved in less than 5 min. The method permits the quantification of albumin and transferrin in IgG concentrates and has been successfully validated.


Natural remission in inflammatory polyarthritis: issues of definition and prediction.
This paper reports the frequency and predictors of remission (no arthritis on examination and no treatment with second-line drugs or steroids within the previous 3 months) in 358 patients with early inflammatory polyarthritis (IP) referred to the Norfolk Arthritis Register. Two years after referral, 91 patients (25%) were in remission, 32 of whom had also been in remission at 1 yr. Remission rates were twice as high in patients with undifferentiated inflammatory polyarthritis at baseline as in those who satisfied criteria for rheumatoid arthritis. To identify predictors of remission, a logistic regression model was developed on a random two-thirds of the patients and validated on the remaining one-third. Remission at 2 yr was associated with male gender and fewer than six tender joints at baseline. However, even the best-fitting model was not sensitive enough to be useful clinically. Thus, amongst patients with early IP in the community, remission rates at 2 yr are low. Further, it was impossible, using simple clinical measures, to predict those patients whose arthritis would resolve.


Metachronous bilateral ectopic breast carcinoma: a case report.
An incomplete regression of the mammary line during embryogenesis occurs in 0.2-6% of the population, which may result in the presence of ectopic breast tissue (EBT). The development of a carcinoma in the EBT is a rare event. The authors present a case report of a 76-year-old female patient, with a lobular carcinoma in an abdominal wall EBT submitted to surgery and adjuvant chemotherapy.


The experience of melanoma follow-up care: an online survey of patients in australia.
Investigating patients' reports on the quality and consistency of melanoma follow-up care in Australia would assist in evaluating if this care is effective and meeting patients' needs. The objective of this study was to obtain and explore the patients' account of the technical and interpersonal aspects of melanoma follow-up care received. An online survey was conducted to acquire details of patients' experience. Participants were patients treated in Australia for primary melanoma. Qualitative and quantitative data about patient perceptions of the nature and quality of their follow-up care were collected, including provision of melanoma specific information, psychosocial support, and imaging tests received. Inconsistencies were reported in the provision and quality of care received. Patient satisfaction was generally low and provision of reassurance from health professionals was construed as an essential element of quality of care. "Gaps" in follow-up care for melanoma patients were identified, particularly provision of adequate psychosocial support and patient education. Focus on strategies for greater consistency in the provision of support, information, and investigations received, may generate a cost dividend which could be reinvested in preventive and supportive care and benefit patient well-being.


Diversity and seasonal dynamics of an assemblage of sarcophagid Diptera in a gradient of urbanization.
Sarcophagid species inhabiting different locations in a rural-urban gradient were surveyed in the east central Argentine district of the Almirante Brown, Buenos Aires province. The main objectives of this research were to identify the most prevalent sarcophagid species and to describe community richness and diversity according to the degree of urbanization and the environmental variables measured in three locations within a rural-urban gradient sampled during two years from May 2005 to April 2007. Spatial and seasonal variations were the main factors involved in structuring the sarcophagid communities. Diversity was lower in urbanized areas than in rural ones. Bait and microhabitat preferences (sunny or shady places) and seasonal fluctuations were described for 17 sarcophagid species.


The Association between Intentional Overdose and Same-Sex Sexual Intercourse in a Cohort of People who Inject Drugs in Melbourne, Australia.
People who inject drugs (PWID) are at disproportionately high risk of suicidal behaviors, as are individuals who report same-sex attraction or experience. However, there is little evidence of compounded risk of suicide for individuals who report same-sex sexual intercourse (SSI) and are PWID. To explore the associations of lifetime intentional overdose amongst a cohort of PWID, with particular attention to those reporting SSI. The sample included 529 participants, from an ongoing cohort of 757 PWID. An "ever" SSI variable was created for participants who reported sexual intercourse with a same-sex partner at any longitudinal interview. We explored the adjusted associations between SSI and lifetime intentional overdose using logistic regression. Ninety-one (17%) participants reported ever experiencing an intentional overdose. Forty-one (8%) participants reported SSI at any interview. Three hundred and sixty (68%) participants reported diagnosis of a mental health condition. Diagnosis of a mental health condition (AOR = 2.02, 95% CIs: 1.14, 3.59) and SSI (AOR = 2.58, 95% CIs: 1.22, 5.48) significantly increased the odds of lifetime intentional overdose. Conclusions/Importance: We found a heightened risk of intentional overdose amongst PWID reporting SSI, after controlling for diagnosis of a mental health condition. Services need to be aware of this heightened risk and target interventions appropriately.


[A case of relapsed small cell lung cancer recognized by simple metastasis to the duodenum].
We describe a case of relapsed small cell lung cancer (SCLC) recognized by a duodenal tumor, its probable metastasis. A 69-year-old man was admitted to Keio University Hospital complaining of persistent sputum production in September, 1996. A diagnosis of SCLC of the left lung invading the mediastinum was based on a transesophageal biopsy. Chemotherapy consisting of CDDP and VP-16 followed by thoracic irradiation at a total dose of 50 Gy was performed from October 1996 to August 1997, resulting in CR (Complete Response) of the tumor. In April of 1999, a mass surrounding the duodenum was found through an abdominal CT survey for tumor relapse, but no other tumors were detected in a series of CT scans or inbone scintigraphy. Subsequent fiberscopy of the upper gastrointestinal tract revealed an ulcerative tumor extensively invading the mucosa of the duodenal bulb. Biopsy specimens obtained from the duodenal tumor showed small-cell carcinoma with features similar to those of SCLC found in 1996, suggesting that SCLC of the left lung metastasized to the duodenal wall. Chemoradiotherapy with 4 cycles of CDDP and VP-16 followed by abdominal irradiation at a dose of 30 Gy was given again from May to September 1999, producing good PR (Partial Response). Although metastasis of SCLC to the duodenum seldom occurs, this report indicates that its early detection and effective treatment may prevent serious symptoms caused by obstruction of the duodenum or the papilla Vater.


Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancers: is there a role?
Hyperthermic intraperitoneal chemotherapy (HIPEC) is often used to treat gastrointestinal malignancies and is of interest in epithelial ovarian cancer (EOC) given the propensity for intraperitoneal spread. The role of HIPEC in the treatment of gynecologic malignancies is not well defined. We sought to describe clinical characteristics and outcomes of our patient population treated with HIPEC. IRB approval was obtained. Patients diagnosed with EOC and treated with HIPEC from January 2007 until December 2013 were identified using a prospectively maintained HIPEC database. Patient charts were abstracted to identify patient demographic information, treatment characteristics, and outcome data. Statistical analysis was descriptive. Thirty-four patients were identified. Mean age at diagnosis was 56.5 years. The majority of cases (28, 82%) were of serous histology. The indications for HIPEC administration were as follows: 9% primary treatment, 41% first recurrence, 26% second recurrence, and 24% consolidative therapy in the setting of primary or recurrent disease. The majority of patients (21, 62%) received mitomycin C. The other drugs administered include cisplatin (10, 29%), oxaliplatin (2, 6%), and carboplatin (1, 3%). Mean length of hospital stay was 9 days (range, 3-39 days). The rates of postoperative bacteremia and hematologic toxicity were 6% and 54%, respectively. Seven (21%) patients developed transient renal dysfunction, and this was seen almost exclusively in the patients who received cisplatin. One (3%) additional patient had renal dysfunction that persisted longer than 30 days post-operative but did not go on to require dialysis. There were no perioperative deaths in this cohort. Eleven (32%) patients received additional chemotherapy following HIPEC administration. At a median follow-up of 20 months (range, 3-87 months), eight patients are alive with disease, seven have no evidence of disease, 14 have died of their disease, and five patients have been lost to follow-up. This data supports a reasonable side effect profile of treatment of EOC with HIPEC. Prospective studies are needed to elucidate the optimal drug and patient population that would derive the most benefit from treatment with HIPEC.


Transanal protrusion of intussusceptions in children.
The aim of the following study is to report our management experience and outcome of transanal protrusion of intussusceptions. Retrospective analysis of all cases of intussusceptions protruding through the anal opening from January 2008 to June 2013. Of 62 cases of intussusceptions, transanal protrusion occurred in 10 patients (16% anal protrusion rate) with a male:female ratio of 2:3. They were aged 4-96 months (mean 22.6 ± 30.7, median 7.5 months). Six were infants while four were above 1 year. Duration of symptoms ranged from 2 to 14 days (mean 5.9 days ± 3.4) with only two patients presenting within 48 h. Clinical features included vomiting (100%), abdominal pains (100%), bloody mucoid stool (100%), abdominal distension (90%), and palpable left iliac fossa mass (70%). Three patients had preceding diarrhoea (30%) and two had preceding upper respiratory tract infection (20%). Duration of hospital stay ranged from 5 to 23 days (mean 12 days ± 5.6). Findings at surgery included seven ileocolic and two colocolic intussusceptions (one patient died before surgery). Operative procedures were right hemicolectomy (5), operative manual reduction (3), left hemicolectomy (1) giving a 67% bowel resection rate. One patient died giving a 10% mortality rate. Transanal protrusion occurred more in females and is associated with late presentation, older age, high bowel resection rate, and high mortality.


Paper-based FRET for the direct detection of collagen triple helix.
In order to develop improved diagnosis and therapies for the highly prevalent chronic fibroproliferative diseases, it is of utmost importance to construct efficient assays to detect collagen biomarkers. We have successfully created a paper-based FRET assay for the fast, inexpensive and direct detection of collagen triple helix. We have demonstrated that the adsorption of the dye-labeled probe peptide onto the GO-immobilized paper quenches the fluorescence of the dye, while the hybridization of the probe peptide with the target collagen peptide results in the desorption of the probe peptide from GO, thus restoring the fluorescence. We have also shown that this novel assay is highly specific to the target collagen peptide sequence with little interference from other proteins, and it can be applied for quantitative detection in complex biological fluids. Our integration of the GO-based FRET assay with a patterned paper provides a powerful new tool for the detection of collagen molecules with many superior features: tiny volumes of samples, multichannel detection mode, easy operation and low-cost equipment. This assay may have promising applications to fast screen multiple target collagen sequences for the discovery of new collagen biomarkers.


Evolution of blind beetles in isolated aquifers: a test of alternative modes of speciation.
Evidence is growing that not only allopatric but also sympatric speciation can be important in the evolution of species. Sympatric speciation has most convincingly been demonstrated in laboratory experiments with bacteria, but field-based evidence is limited to a few cases. The recently discovered plethora of subterranean diving beetle species in isolated aquifers in the arid interior of Australia offers a unique opportunity to evaluate alternative modes of speciation. This naturally replicated evolutionary experiment started 10-5 million years ago, when climate change forced the surface species to occupy geographically isolated subterranean aquifers. Using phylogenetic analysis, we determine the frequency of aquifers containing closely related sister species. By comparing observed frequencies with predictions from different statistical models, we show that it is very unlikely that the high number of sympatrically occurring sister species can be explained by a combination of allopatric evolution and repeated colonisations alone. Thus, diversification has occurred within the aquifers and likely involved sympatric, parapatric and/or microallopatric speciation.


Negative mood reverses devaluation of goal-directed drug-seeking favouring an incentive learning account of drug dependence.
Two theories explain how negative mood primes smoking behaviour. The stimulus-response (S-R) account argues that in the negative mood state, smoking is experienced as more reinforcing, establishing a direct (automatic) association between the negative mood state and smoking behaviour. By contrast, the incentive learning account argues that in the negative mood state smoking is expected to be more reinforcing, which integrates with instrumental knowledge of the response required to produce that outcome. One differential prediction is that whereas the incentive learning account anticipates that negative mood induction could augment a novel tobacco-seeking response in an extinction test, the S-R account could not explain this effect because the extinction test prevents S-R learning by omitting experience of the reinforcer. To test this, overnight-deprived daily smokers (n = 44) acquired two instrumental responses for tobacco and chocolate points, respectively, before smoking to satiety. Half then received negative mood induction to raise the expected value of tobacco, opposing satiety, whilst the remainder received positive mood induction. Finally, a choice between tobacco and chocolate was measured in extinction to test whether negative mood could augment tobacco choice, opposing satiety, in the absence of direct experience of tobacco reinforcement. Negative mood induction not only abolished the devaluation of tobacco choice, but participants with a significant increase in negative mood increased their tobacco choice in extinction, despite satiety. These findings suggest that negative mood augments drug-seeking by raising the expected value of the drug through incentive learning, rather than through automatic S-R control.


Critical and honest conversations: the evidence behind the "Choosing Wisely" campaign recommendations by the American Society of Nephrology.
Estimates suggest that one third of United States health care spending results from overuse or misuse of tests, procedures, and therapies. The American Board of Internal Medicine Foundation, in partnership with Consumer Reports, initiated the "Choosing Wisely" campaign to identify areas in patient care and resource use most open to improvement. Nine subspecialty organizations joined the campaign; each organization identified five tests, procedures, or therapies that are overused, are misused, or could potentially lead to harm or unnecessary health care spending. Each of the American Society of Nephrology's (ASN's) 10 advisory groups submitted recommendations for inclusion. The ASN Quality and Patient Safety Task Force selected five recommendations based on relevance and importance to individuals with kidney disease.Recommendations selected were: (1) Do not perform routine cancer screening for dialysis patients with limited life expectancies without signs or symptoms; (2) do not administer erythropoiesis-stimulating agents to CKD patients with hemoglobin levels ≥10 g/dl without symptoms of anemia; (3) avoid nonsteroidal anti-inflammatory drugs in individuals with hypertension, heart failure, or CKD of all causes, including diabetes; (4) do not place peripherally inserted central catheters in stage 3-5 CKD patients without consulting nephrology; (5) do not initiate chronic dialysis without ensuring a shared decision-making process between patients, their families, and their physicians.These five recommendations and supporting evidence give providers information to facilitate prudent care decisions and empower patients to actively participate in critical, honest conversations about their care, potentially reducing unnecessary health care spending and preventing harm.


Diuretic use is associated with better learning and memory in older adults in the Ginkgo Evaluation of Memory Study.
To investigate the association between diuretics, angiotensin-converting enzyme inhibitors (ACE-I), angiotensin II receptor blockers (AT2RB), and cognitive function. This post hoc analysis of the randomized controlled Ginkgo Evaluation of Memory Study trial focuses on 3069 nondemented community-dwelling participants aged >75 years. At baseline visit, detailed information about medication use was collected and five cognitive domains were assessed. Multivariate linear regression analyses were used to assess cross-sectional associations between medication use and cognitive function. In all, 36% of participants reported history of hypertension and 53% reported antihypertensive medication use, with 17% reporting diuretic, 11% ACE-I, and 2% AT2RB use. Potassium-sparing diuretic use (N = 192) was associated with better verbal learning and memory measured by California Verbal Learning Test as compared with no antihypertensive medication users (β = 0.068, P = .01; β = 0.094, P < .001) and other antihypertensive medication users (β = 0.080, P = .03; β = 0.153, P < .001). Use of ACE-I or AT2RB was not associated with better cognitive function. Results warrant further investigation into possible protective effects of potassium-sparing diuretics and the role of potassium in mitigating cognitive decline.


Ultrasonic Sensors Enabling Early Detection of Emergency Trends and Analysis of Structure Inclination and Stability by Means of Highly Accurate Level Measurements.
Building inclinations can be measured through the use of ultrasonic hydrostatic levelers. These are used to measure long-term relative displacements of vertical parts of structures and utilize the principle of communicating vessels (similar to the classic water scales). The presented ultrasonic displacement measurement technique was developed by Ultrasystem in the 1990s and was applied to several objects in Poland. Long-term measurements enabled the development of a model of object behavior under the influence of various factors. Among these are the annual cycle of temperature changes, fluctuating water levels, turbine chamber emptying, etc. Such a model can facilitate the prediction of failure based on the appearance of changes deviating from typical behavior (e.g., a much stronger dependence of the inclination as a function of the water level). The results obtained with the help of ultrasonic sensors enable the observation of subtle deformations of the object, which is valuable when developing and calibrating new models of the object (e.g., by means of the finite element method).


Synthesis and Characterization of AICAR and DOX Conjugated Multifunctional Nanoparticles as a Platform for Synergistic Inhibition of Cancer Cell Growth.
The success of cancer treatment depends on the response to chemotherapeutic agents. However, malignancies often acquire resistance to drugs if they are used frequently. Combination therapy involving both a chemotherapeutic agent and molecularly targeted therapy may have the ability to retain and enhance therapeutic efficacy. Here, we addressed this issue by examining the efficacy of a novel therapeutic strategy that combines AICAR and DOX within a multifunctional platform. In this context, we reported the bottom-up synthesis of Fe3O4@SiO2(FITC)-FA/AICAR/DOX multifunctional nanoparticles aiming to neutralize survivin (BIRC5) to potentiate the efficacy of DOX against chemoresistance. The structure of nanoparticles was characterized by dynamic light scattering (DLS), zeta-potential measurement, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), and electron microscopy (SEM and STEM with EDX) techniques. Cellular uptake and cytotoxicity experiments demonstrated preferentially targeted delivery of nanoparticles and an efficient reduction of cancer cell viability in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat, and MIA PaCa-2). These results indicate that the multifunctional nanoparticle system possesses high inhibitory drug association and sustained cytotoxic effect with good biocompatibility. This novel approach which combines AICAR and DOX within a single platform might be promising as an antitumor treatment for cancer.


Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) is characterised by the development of numerous colorectal adenomatous polyps. Other extracolonic benign or malignant lesions have been reported previously in association with FAP but precancerous lesions in the pancreas have never been described. We report the first case of intraductal papillary and mucinous pancreatic tumour (IPMT) in a patient with FAP. A 48 year old man with a well documented past history of FAP was admitted for epigastric pain, weight loss, and new onset diabetes mellitus. Spiral computed tomography scan revealed a large tumour in the pancreatic head with upstream main pancreatic duct dilatation. Endoscopic ultrasonography confirmed these data. Mucous secretion was seen at duodenoscopy and a lesion in the main pancreatic duct was confirmed by retrograde pancreatography. The patient underwent a pancreaticoduodenectomy for suspected IPMT. Histological examination of the resected specimen confirmed an IPMT with in situ carcinoma. Twelve months after resection, the patient remained free of tumour relapse. Genetic analysis showed loss of the wild allele of the adenomatous polyposis coli gene in IPMT, causing inactivation of both alleles and demonstrating that IPMT was not incidental in this patient. IPMT should be included in the extracolonic localisation of FAP.


Geriatric assessment with management for older patients with cancer receiving radiotherapy. Protocol of a Norwegian cluster-randomised controlled pilot study.
About 50% of patients with cancer are expected to need radiotherapy (RT), and the majority of these are older. To improve outcomes for older patients with cancer, geriatric assessment (GA) with management (GAM) is highly recommended. Evidence for its benefits is still scarce, in particular for patients receiving RT. We report the protocol of a cluster-randomised pilot study designed to test the effect, feasibility and health economic impact of a GAM intervention for patients ≥65 years, referred for palliative or curative RT. The randomising units are municipalities and city districts. The intervention is municipality-based and carried out in collaboration between hospital and municipal health services from the start of RT to eight weeks after the end of RT. Its main constituents are an initial GA followed by measures adapted to individual patients' impairments and needs, systematic symptom assessments and regular follow-up by municipal cancer nurses, appointed to coordinate the patient's care. Follow-up includes at least one weekly phone call, and a house call four weeks after the end of RT. All patients receive an individually adapted physical exercise program and nutritional counselling. Detailed guidelines for management of patients' impairments are provided. Patients allocated to the intervention group will be compared to controls receiving standard care. The primary outcome is physical function assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire C-30. Secondary outcomes are global quality of life, objectively tested physical performance and use of health care services. Economic evaluation will be based on a comparison of costs and effects (measured by the main outcome measures). Feasibility will be assessed with mixed methodology, based on log notes and questionnaires filled in by the municipal nurses and interviews with patients and nurses. The study is carried out at two Norwegian RT centres. It was opened in May 2019. Follow-up will proceed until June 2022. Statistical analyses will start by the end of 2021. We expect the trial to provide important new knowledge about the effect, feasibility and costs of a GAM intervention for older patients receiving RT. Trial registration: ClinTrials.gov, ID NCT03881137, initial release 13th of March 2019.


Financial stress and outcomes after acute myocardial infarction.
Little is known about the association between financial stress and health care outcomes. Our objective was to examine the association between self-reported financial stress during initial hospitalization and long-term outcomes after acute myocardial infarction (AMI). We used prospective registry evaluating myocardial infarction: Event and Recovery (PREMIER) data, an observational, multicenter US study of AMI patients discharged between January 2003 and June 2004. Primary outcomes were disease-specific and generic health status outcomes at 1 year (symptoms, function, and quality of life (QoL)), assessed by the Seattle Angina Questionnaire [SAQ] and Short Form [SF]-12. Secondary outcomes included 1-year rehospitalization and 4-year mortality. Hierarchical regression models accounted for patient socio-demographic, clinical, and quality of care characteristics, and access and barriers to care. Among 2344 AMI patients, 1241 (52.9%) reported no financial stress, 735 (31.4%) reported low financial stress, and 368 (15.7%) reported high financial stress. When comparing individuals reporting low financial stress to no financial stress, there were no significant differences in post-AMI outcomes. In contrast, individuals reporting high financial stress were more likely to have worse physical health (SF-12 PCS mean difference -3.24, 95% Confidence Interval [CI]: -4.82, -1.66), mental health (SF-12 MCS mean difference: -2.44, 95% CI: -3.83, -1.05), disease-specific QoL (SAQ QoL mean difference: -6.99, 95% CI: -9.59, -4.40), and be experiencing angina (SAQ Angina Relative Risk = 1.66, 95%CI: 1.19, 2.32) at 1 year post-AMI. While 1-year readmission rates were increased (Hazard Ratio = 1.50; 95%CI: 1.20, 1.86), 4-year mortality was no different. High financial stress is common and an important risk factor for worse long-term outcomes post-AMI, independent of access and barriers to care.


Massive allografts in the treatment of osteosarcoma and Ewing sarcoma in children and adolescents.
A retrospective review was performed of the results of all allograft reconstructions that had been done after the resection of an osteosarcoma or an Ewing sarcoma in a skeletally immature patient between 1982 and 1989 at The Hospital for Sick Children in Toronto. There were twenty-six patients. Six reconstructions were intercalary, sixteen were resection arthrodeses, three followed resection of a bone segment including the epiphysis (osteoarticular reconstruction), and one was a replacement of the entire humerus. Resection arthrodesis about the knee was performed with a smooth intramedullary rod and with one growth plate left intact. Six procedures were performed in the upper extremity. Excluding the patients who died, the average duration of follow-up was five years and three months. Twenty-one of the twenty-six patients had reached skeletal maturity at the time of follow-up. Eighteen (69 per cent) of the patients had a good or excellent result, four (15 per cent) had a fair result, and four had a failure. Twenty patients (77 per cent) had at least one complication (other than a limb-length discrepancy), and fourteen (54 per cent) sustained at least one fracture of the allograft. Fifteen patients who had had a reconstruction in the lower extremity had survived with survival of the allograft at the time of the latest follow-up. A limb-length discrepancy of at least two centimeters developed in nine of the fifteen patients. Five were managed with a contralateral epiphyseodesis, and one of them had an unsuccessful attempt at limb-lengthening as well. The patients who had a limb-length discrepancy of more than three centimeters at the time of follow-up had been significantly younger (p < 0.05) at the time of the reconstruction than those who had a smaller discrepancy. Three allografts (12 per cent), two of which were implanted early in the series, became infected. Soft-tissue coverage is of paramount importance for the prevention of infection, and we now routinely perform primary muscle (gastrocnemius or latissimus dorsi) transfers when dealing with an inadequate muscle envelope. Twelve patients were followed for more than four years (average, six years and seven months); they had no complications other than increased limb-length discrepancy and one subluxation of the shoulder after the first four years following the reconstruction. Although the rate of complications is higher than in adults, allograft reconstruction remains a useful option for the management of skeletally immature individuals.(ABSTRACT TRUNCATED AT 400 WORDS)


Cytokinin induces cell division in the quiescent center of the Arabidopsis root apical meristem.
In the root apical meristem, which contains the stem cells that feed into root development, the phytohormones auxin and cytokinin play opposing roles, with auxin promoting cell division and cytokinin promoting cell differentiation. Cytokinin acts in the root tip in part by modulating auxin transport through regulation of the level of the PIN auxin efflux carriers. Auxin plays a key role in the specification of the quiescent center (QC), which is essential for maintaining the stem cell fate of the surrounding cells. We demonstrate that cytokinin promotes cell division in the QC, which is generally mitotically inactive. Cytokinin downregulates the expression of several key regulatory genes in the root tip, including SCARECROW, WOX5, and the auxin influx carriers AUX1 and LAX2. The decrease in LAX2 expression in response to cytokinin requires ARR1 and ARR12, two type B ARRs that mediate the primary transcriptional response to cytokinin. ARR1 was found to bind directly to the LAX2 gene in vivo, which indicates that type B ARRs directly regulate genes that are repressed by cytokinin. Disruption of the LAX2 gene results in a phenotype similar to that observed in response to cytokinin, including increased division of the cells in the QC and decreased expression of WOX5 and the auxin response reporter DR5. Cytokinin acts to regulate auxin distribution in the root apical meristem by regulating both the PINs and LAX2. This redistribution of auxin, potentially coupled with other auxin-independent effects of cytokinin, regulates the mitotic activity in the QC.


Ten-year incidence rates of age-related cataract in the Age-Related Eye Disease Study (AREDS): AREDS report no. 33.
To investigate the long-term incidence of age-related cataract and cataract surgery in the Age-Related Eye Disease Study (AREDS) cohort. Baseline and annual lens photographs of participants, aged 55-80 years, were graded centrally for nuclear, cortical, and posterior subcapsular (PSC) lens opacities using the AREDS System for Classifying Cataracts. Progression from a baseline status of no or mild lens opacity to at least moderate severity was analyzed and cumulative incidence estimated rates were calculated for each lens opacity type and cataract surgery stratified by age, sex, race, age-related macular degeneration category, multivitamin (Centrum) use and history of diabetes. The ten-year cumulative incidence was 43.6% for any cataract, 23.1% for nuclear cataract, 22.0% for cortical cataract, 13.1% for PSC cataract, and 26.8% for cataract surgery. The 5- and 10-year incidence rates of all cataract types and cataract surgery were significantly higher with increasing age. Females had a higher incidence of any, nuclear and cortical cataract and cataract surgery (p = 0.02-0.05). Incidence of cortical cataract was higher in non-white participants (p = 0.001). These results are largely consistent with the results of previous observational studies. Long-term incidence rates of type-specific cataract can be useful in designing clinical studies of age-related cataract.


Effects of Ceratomyxa shasta dose on a susceptible strain of rainbow trout and comparatively resistant Chinook and coho salmon.
Ceratomyxa shasta infects salmon and trout, causing ceratomyxosis, a disease characterized by parasite proliferation in the intestine and death. We used laboratory challenges to investigate the infective dose for 3 fish species: a susceptible strain of rainbow trout Oncorhynchus mykiss and comparatively resistant Chinook O. tshawytscha and coho salmon O. kisutch. For susceptible rainbow trout, we determined the outcome of infection under conditions of varying parasite dose, fish size, and parasite concentration. A single actinospore was sufficient to cause a lethal infection in susceptible rainbow trout. The mean days to death (MDD) did not significantly decrease among doses causing 100% prevalence, indicating a minimum time required for parasites to replicate to a fatal level. When dose was constant, but delivered in a higher parasite concentration, higher infection prevalence and mortality resulted. One actinospore fish(-1) caused 57% infection and mortality in fish challenged in 0.5 1 of water, whereas 10 spores fish(-1) resulted in an average of 49% infection and mortality in 1 l challenges. This effect is most likely due to a higher encounter rate in the smaller water volume. Neither infection prevalence nor MDD was significantly different between large trout (84.9 g) and small trout (6.3 g). Chinook salmon did not become infected even when challenged with 5000 actinospores. One fatal infection occurred in coho salmon challenged with 1000 actinospores. This study confirms that even low doses of C. shasta cause severe infection in highly susceptible fish, describes the dose response on MDD, and demonstrates that parasite concentration influences infection prevalence.


Use of medications to decrease bleeding during surgical abortion: a survey of abortion providers' practices in the United States.
Our objective was to document current practices of abortion providers on the use of medications to decrease bleeding during surgical abortion. We emailed surveys to 336 abortion providers through a professional listserv to elicit information on their use of medications to prevent and treat bleeding during first- and second-trimester surgical abortion. One hundred sixty-eight (50%) providers responded to our survey. The majority were obstetrician-gynecologists (83%) working in an academic practice (66%). Most completed a fellowship in family planning (87%) and currently perform abortions up to 22 or 24weeks of gestation (63%). Seventy-two percent routinely used prophylactic medications for bleeding. Providers who routinely used medications to prevent bleeding most commonly chose vasopressin (83%). Providers preferred methylergonovine as a treatment for excessive bleeding in the second trimester, followed by misoprostol. We found that most providers routinely use medications to prevent bleeding and use several different regimens to treat bleeding during abortion. We found that surgical abortion providers use a range of medications to prevent and treat hemorrhage at the time of surgical abortion. Scant evidence is available to guide abortion providers on the use of medications to decrease hemorrhage during surgical abortion. To provide evidence-based recommendations for the prevention and treatment of clinically significant bleeding, researchers should target the most commonly used interventions.


Switching from Controlled Ring-Opening Polymerization (cROP) to Controlled Ring-Closing Depolymerization (cRCDP) by Adjusting the Reaction Parameters That Determine the Ceiling Temperature.
Full control over the ceiling temperature (Tc) enables a selective transition between the monomeric and polymeric state. This is exemplified by the conversion of the monomer 2-allyloxymethyl-2-ethyl-trimethylene carbonate (AOMEC) to poly(AOMEC) and back to AOMEC within 10 h by controlling the reaction from conditions that favor ring-opening polymerization (Tc > T0) (where T0 is the reaction temperature) to conditions that favor ring-closing depolymerization (Tc < T0). The ring-closing depolymerization (RCDP) mirrors the polymerization behavior with a clear relation between the monomer concentration and the molecular weight of the polymer, indicating that RCDP occurs at the chain end. The Tc of the polymerization system is highly dependent on the nature of the solvent, for example, in toluene, the Tc of AOMEC is 234 °C and in acetonitrile Tc = 142 °C at the same initial monomer concentration of 2 M. The control over the monomer to polymer equilibrium sets new standards for the selective degradation of polymers, the controlled release of active components, monomer synthesis and material recycling. In particular, the knowledge of the monomer to polymer equilibrium of polymers in solution under selected environmental conditions is of paramount importance for in vivo applications, where the polymer chain is subjected to both high dilution and a high polarity medium in the presence of catalysts, that is, very different conditions from which the polymer was formed.


Treatment of diffuse large B-cell lymphoma in the elderly: regimens without anthracyclines are common and not futile.
Anthracycline-containing regimens (ACRs) are recommended for patients with diffuse large B-cell lymphoma (DLBCL). However, over 40% of elderly patients do not receive ACRs, possibly due to expected toxicities. We characterized treatment choices and compared the 3-year overall survival (OS) rates of 8262 Medicare beneficiaries diagnosed with DLBCL in 2000-2006 identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Of the cohort, 45% had ACR with rituximab (ACR-R), 13% had ACR without R, 6% had non-ACR with R (non-ACR-R), 4% had R monotherapy, 3% had non-ACR and 29% had no systemic therapy. Patients not receiving ACR were older and/or had more comorbidities. The unadjusted OS was highest in ACR-R (65%), followed by ACR without R (55%) and non-ACR-R (44%). After adjusting patient covariates, ACR-R showed the best survival (63%). However, OS was comparable between non-ACR-R (52%) and ACR without R (52%). Non-ACR-R could be considered for patients who are poor candidates for ACR.


Cervical carcinosarcoma presented in advanced stage after high grade cervical displasia.
Cervical carcinosarcomas (Malignant Mixed Mullerian Tumour [MMMT] ) are very rare neoplasms. Fewer than 100 cases were documented until recently. Because of the rarity, etiologic factors, prognosis and treatment modalities are unclear. A 53 year-old woman presented with postmenauposal vaginal bleeding and abnormal cervical cytology. Cervical biopsy followed by loop electrosurgical excision procedure (LEEP) and cold knife conisation (CKC) was documented as cervical intraepithelial neoplasia III (CIN III). Without follow-up, two years later, the patient was referred with a cervical 6,5 cm mass invading vagina, parametriums and rectum. Biopsy was reported as cervical carcinosarcoma with squmous carcinoma and homologous sarcoma component. Neoadjuvant chemotherapy provided partial response. Subsequently external beam whole pelvis radiotherapy with chemotherapy and brachytherapy was applied. In despite of the treatment, the patient developed sistemic recurrence and died of disease within 10 months. In previous reports most of the patients were in early stage and had better prognosis than uterine carcinosarcomas. Here in we present a case who had a history of high-grade cervical displasia and presented at advanced stage, managed with neoadjuvant chemotherapy and definitive chemoradiotherapy.


Case of severe acute hepatitis A virus infection in United Nations peacekeepers in South Sudan.
Hepatitis A virus (HAV) is a major cause of acute viral hepatitis, which can lead to severe cases and acute liver failure. A 41-year-old Chinese military officer of the United Nations peacekeeping forces in South Sudan manifested fever, jaundice and coagulation dysfunction. The patient initially had a negative anti-HAV IgM antibody test result but a positive anti-HAV-IgM antibody test result five days after his alanine aminotransferase (ALT) levels peaked. He was given telemedicine consultation and was transferred to a Chinese military hospital specialising in infectious diseases for treatment of severe acute HAV infection. The peak ALT, aspartate aminotransferase, total bilirubin and international standard ratio were 5410 U/L, 3475 U/L, 225.1 µmol/L and 2.12 during hospitalisation, respectively. Military personnel undergoing missions in areas with high prevalence of HAV should be tested for previous HAV infection before departure if they have not been previously vaccinated. If negative results are obtained, they should be vaccinated. Anti-HAV-IgM examination should be repeated after the first negative test result is obtained to eliminate the effects of a window period if a clinical suspicion exists. If a life-threatening case of HAV infection is present, the patient should be transported to a base military hospital specialising in infectious diseases for treatment.


Three years of "CASMS": the world's busiest medical simulation centre.
Medical simulation is a relatively new teaching modality suitable for medical education at all levels, although its long-term benefits have not yet been validated. Simulation allows the participant to practise diagnosis, medical management and behavioural approaches in the care of acutely ill patients in a controlled environment. Simulators have achieved widespread acceptance in the fields of anaesthesia, intensive care and emergency medicine. More recently, team training for pre-hospital and within-hospital multidisciplinary medical response teams has become popular. The increasing number and diversity of courses at "CASMS" parallels the evolution of simulation centres into regional clinical skills centres elsewhere. Such centres are likely to become a cost-effective means of achieving greater consistency in medical skill acquisition and may improve patient outcomes after medical crises.


Tocopherols in cancer: An update.
Tocopherols exist in four forms designated as α, β, δ, and γ. Due to their strong antioxidant properties, tocopherols have been suggested to reduce the risk of cancer. Cancer prevention studies with tocopherols have mostly utilized α-tocopherol. Large-scale clinical trials with α-tocopherol provided inconsistent results regarding the cancer-preventive activities of tocopherols. This review summarizes our current understanding of the anticancer activities of different forms of tocopherols based on follow-up of the clinical trials, recent epidemiological evidences, and experimental studies using in vitro and in vivo models. The experimental data provide strong evidence in support of the anticancer activities of δ-tocopherol, γ-tocopherol, and the natural tocopherol mixture rich in γ-tocopherol, γ-TmT, over α-tocopherol. Such outcomes emphasize the need for detailed investigation into the cancer-preventive activities of different forms of tocopherols to provide a strong rationale for intervention studies in the future.


The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5.
Tumor hypoxia is a common microenvironmental factor that adversely influences tumor phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). Recent reports have indicated that hypoxia activates a lysosomal degradation pathway known as autophagy, and here we show that the UPR enhances the capacity of hypoxic tumor cells to carry out autophagy, and that this promotes their survival. In several human cancer cell lines, hypoxia increased transcription of the essential autophagy genes microtubule-associated protein 1 light chain 3beta (MAP1LC3B) and autophagy-related gene 5 (ATG5) through the transcription factors ATF4 and CHOP, respectively, which are regulated by PKR-like ER kinase (PERK, also known as EIF2AK3). MAP1LC3B and ATG5 are not required for initiation of autophagy but mediate phagophore expansion and autophagosome formation. We observed that transcriptional induction of MAP1LC3B replenished MAP1LC3B protein that was turned over during extensive hypoxia-induced autophagy. Correspondingly, cells deficient in PERK signaling failed to transcriptionally induce MAP1LC3B and became rapidly depleted of MAP1LC3B protein during hypoxia. Consistent with these data, autophagy and MAP1LC3B induction occurred preferentially in hypoxic regions of human tumor xenografts. Furthermore, pharmacological inhibition of autophagy sensitized human tumor cells to hypoxia, reduced the fraction of viable hypoxic tumor cells, and sensitized xenografted human tumors to irradiation. Our data therefore demonstrate that the UPR is an important mediator of the hypoxic tumor microenvironment and that it contributes to resistance to treatment through its ability to facilitate autophagy.


Buccal epithelial cell micronuclei: Sensitive, non-invasive biomarkers of occupational exposure to low doses of ionizing radiation.
We have evaluated buccal epithelial cell micronucleus formation as a biomarker of genotoxic damage following occupational exposure to low doses of ionizing radiation. Buccal epithelial cells were collected from 42 occupationally exposed medical personnel and 39 non-exposed individuals (reference group). Each individual in the exposed group was routinely monitored with a personal radiation badge. The frequency of micronucleated cells (MNC) was significantly higher in the exposed group (5.26 vs. 1.33 MNC/2000 cells) and correlated strongly with accumulated radiation dose (Annual Deep Dose, mSv). Occupational exposure to low doses of ionizing radiation was associated with an 80% relative increase in the frequency of MNC (MRR = 1.8; 95% CI: 1.1-2.8), suggesting that such exposures cause DNA damage. This non-invasive biomonitoring method should be generally applicable to studies of workers who are exposed occupationally to low doses of IR.


Functional characterisation of Schistosoma japonicum acetylcholinesterase.
Acetylcholinesterase (AChE) is an important metabolic enzyme of schistosomes present in the musculature and on the surface of the blood stage where it has been implicated in the modulation of glucose scavenging from mammalian host blood. As both a target for the antischistosomal drug metrifonate and as a potential vaccine candidate, AChE has been characterised in the schistosome species Schistosoma mansoni, S. haematobium and S. bovis, but not in S. japonicum. Recently, using a schistosome protein microarray, a predicted S. japonicum acetylcholinesterase precursor was significantly targeted by protective IgG1 immune responses in S. haematobium-exposed individuals that had acquired drug-induced resistance to schistosomiasis after praziquantel treatment. We report the full-length cDNA sequence and describe phylogenetic and molecular structural analysis to facilitate understanding of the biological function of AChE (SjAChE) in S. japonicum. The protein has high sequence identity (88 %) with the AChEs in S. mansoni, S. haematobium and S. bovis and has 25 % sequence similarity with human AChE, suggestive of a highly specialised role for the enzyme in both parasite and host. We immunolocalized SjAChE and demonstrated its presence on the surface of adult worms and schistosomula, as well as its lower expression in parenchymal regions. The relatively abundance of AChE activity (90 %) present on the surface of adult S. japonicum when compared with that reported in other schistosomes suggests SjAChE may be a more effective drug or immunological target against this species. We also demonstrate that the classical inhibitor of AChE, BW285c51, inhibited AChE activity in tegumental extracts of paired worms, single males and single females by 59, 22 and 50 %, respectively, after 24 h incubation with 200 μM BW284c51. These results build on previous studies in other schistosome species indicating major differences in the enzyme between parasite and mammalian host, and provide further support for the design of an anti-schistosome intervention targeting AChE.


Health behaviors in cancer survivors.
To describe health behaviors of cancer survivors by cancer diagnosis and to compare them to people without a personal or family cancer history. Cross-sectional secondary data analysis. A national, list-assisted telephone survey using random-digit dialing of U.S. adults about use of cancer-related information and cancer beliefs. 619 cancer survivors and 2,141 participants without a history of cancer from the original 6,369 Health Information National Trends Survey (HINTS) respondents. Using the National Cancer Institute's 2003 HINTS, further analyses were conducted. Cancer history, current smoking, fruit and vegetable consumption, physical activity, and body mass index (BMI). When controlling for demographic variables, no differences were found in self-reported health behaviors between survivors and those without cancer: 22.5% of survivors and 18.4% of those without cancer were current smokers, 18% of survivors and 14.9% of those without cancer consumed at least five fruits or vegetables per day, 45.3% of survivors and 53% of those without cancer were physically active at least weekly, and 58% of survivors and 54.9% of those without cancer were overweight or obese (i.e., BMI > 25). Only 7.4% of survivors and 6.4% of participants without cancer reported positively on all three health behaviors and had a healthy or normal weight. Survivors did not have different health behaviors when compared to participants without a history of cancer. Neither group met the American Cancer Society or Healthy People 2010 objectives for these behaviors. Adoption of healthy lifestyle behaviors should be addressed in cancer survivors. Cancer survivors need to be assessed for current smoking, dietary habits, physical activity, and weight. Information and resources should be made available, if needed, to promote the adoption of healthy lifestyle behaviors.


Methadone and buprenorphine prescribing patterns of Victorian general practitioners: their first 5 years after authorisation.
The use of opioid substitution therapy (OST) is a widely used and effective treatment for opioid dependence, yet many Australian general practitioners (GPs) authorised to administer OST, prescribe to very few or no patients. This is a particular issue within Victoria that places greater reliance on a small number of active OST prescribing GPs, compared with other jurisdictions. Given the unmet demand for treatment, the provision of accurate figures on the OST prescribing practices of Victorian GPs is necessary for workforce planning. This study aimed to ascertain information on the prescribing patterns of Victorian GPs in their first 5 years after training, and elicit any trends that may explain their reluctance to prescribe OST. The prescribing patterns over a 5 year period of 168 Victorian GPs who became first authorised to prescribe OST during the years 2001-2004 were examined by accessing the Victorian Department of Human Services OST individual patient treatment permit data. Forty-six per cent of these GPs never held a patient permit, and at any one time, approximately two-thirds did not hold a permit. The majority of active prescribers were treating fewer than 10 patients and only 12.5% ever prescribed to more than 50 patients. The study suggests the Victorian GP workforce is inadequate to address the demand for OST. Many more GPs will need to be recruited, and encouraged to prescribe for more patients. Further research is required to identify barriers to GP OST prescribing.


Prolonged inflammation leads to ongoing damage after spinal cord injury.
The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.


Effects of short-term supplementation with coenzyme Q10 on myocardial protection during cardiac operations.
Coenzyme Q10 (CoQ10) is a naturally occurring vitamin-like substance that may have a beneficial role in ischemia-reperfusion injury. Coenzyme Q10 administered either as an additive to cardioplegia or as long-term preoperative oral supplementation has been reported to ameliorate myocardial injury after cardiac operations. To determine whether short-term supplementation with large doses of CoQ10 (600 mg in divided doses 12 hours before operation) was effective in myocardial protection, 20 patients with well-preserved left ventricular function (ejection fraction greater than 0.50) undergoing elective coronary revascularization were enrolled in a prospective, double-blind, placebo-controlled randomized trial. Serial concentrations of CoQ10, myoglobin, creatine kinase MD fraction, and cardiac troponin T were measured preoperatively and 1, 6, 24, 72, and 120 hours postoperatively. Efficacy of myocardial protection was also assessed by clinical outcome and serial changes in electrocardiographic indices. The patient groups were similar with respect to preoperative and intraoperative characteristics. There was no significant difference in the preoperative plasma levels of CoQ10. These levels fell significantly in both groups after operation, although the magnitude of the decrease was less in the CoQ10-supplemented group (43% versus 60%). In both groups, there were significant postoperative increases in myoglobin, creatine kinase MB fraction, and cardiac troponin T. The magnitude of increases in cardiac troponin T was greater in the CoQ10-supplemented group, reaching marginal overall statistical significance (p = 0.06). Short-term supplementation with large doses of CoQ10 does not lead to improved myocardial protection in patients undergoing coronary revascularization with well-preserved ventricular function and relatively short ischemic times.


Computer tool FUNSITE for analysis of eukaryotic regulatory genomic sequences.
We present the computer tool FUNSITE for description and analysis of regulatory sequences of eukaryotic genomes. The tool consists of the following main parts: 1) An integrated database for genomic regulatory sequences. The integrated database was designed on the basis of the databases TRANSFAC (Wingender 1994) and TRRD (Kel et al. 1995) that are currently under development. The following functions are performed: i) linkage to the EMBL database; ii) preparing samples of definite types of functional sites with their flanking sequences; iii) preparing samples of promoter sequences; iv) preparing samples of transcription factors classified with regard to structural and functional features of DNA binding and activating domains, functional families of the factors, their tissue specificity and other functional features; v) access to data on mutual disposition of cis-elements within the regulatory regions. 2) The second component of FUNSITE tool is the set of programs for analysis of the structural organization of regulatory sequences: i) Program for revealing of potential transcription factors binding sites based on their consensi; ii) program for revealing of the potential binding sites using homology search with nucleotide sequences of real binding sites; iii) program for analysis of oligonucleotide context features which are characteristic of flank sequences of the binding sites; iv) program for design of recognition method for the functional sites based on generalized weight matrix; v) program for revealing potential composite elements. The results of analysis of the promoter sequences of eukaryotic genes with the FUNSITE are presented, too.


Prevention of Bloodstream Infections in Patients Undergoing Hemodialysis.
Bloodstream infections are an important cause of hospitalizations, morbidity, and mortality in patients receiving hemodialysis. Eliminating bloodstream infections in the hemodialysis setting has been the focus of the Centers for Disease Control and Prevention (CDC) Making Dialysis Safer for Patients Coalition and, more recently, the CDC's partnership with the American Society of Nephrology's Nephrologists Transforming Dialysis Safety Initiative. The majority of vascular access-associated bloodstream infections occur in patients dialyzing with central vein catheters. The CDC's core interventions for bloodstream infection prevention are the gold standard for catheter care in the hemodialysis setting and have been proven to be effective in reducing catheter-associated bloodstream infection. However, in the United States hemodialysis catheter-associated bloodstream infections continue to occur at unacceptable rates, possibly because of lapses in adherence to strict aseptic technique, or additional factors not addressed by the CDC's core interventions. There is a clear need for novel prophylactic therapies. This review highlights the recent advances and includes a discussion about the potential limitations and adverse effects associated with each option.