Dissociation and catalysis in yeast hexokinase A.
1. The specific activity of yeast hexokinase A depends on the concentration of the protein in the solution being assayed. When a solution containing 13.5 mg of hexokinase A/ml is diluted 10--100-fold at various values of pH and temperature, there is a gradual decline in the specific activity of the enzyme until an equilibrium value is reached, which varies with the chosen experimental conditions. 2. The catalytic activity lost when hexokinase A (1 mg/ml) is incubated at 30degreesC is recovered by lowering the temperature to 25degreesC. 3. These concentration- and temperature-dependent phenomena are consistent with the existence of a monomer-dimer equilibrium in which the dimer alone is the catalytic form of the enzyme. 4. Glucose alone prevents the decline in specific activity of hexokinase A after dilution, but it does not re-activate dilute solutions solutions of the enzyme. It is concluded that glucose binds to both the dimer and the monomer and prevents both association and dissociation. 5. The progress curve describing the phosphorylation of glucose catalysed by hexokinase A does not attain a steady state. It is possible that dissociation of catalytically active dimers in a ternary complex with glucose and ATP (or glucose 6-phosphate and ADP) could explain the non-linearity of this progress curve.


Mammography correlates to better survival rates in breast cancer patients: a 20-year experience in a University health institution.
Breast cancer (BC) is the most common malignancy in women. We retrieved medical records from >2,000 Chilean BC patients over the 1997-2018 period. The objective was to assess changes in clinical presentation or prognosis of our patients throughout these 20 years of practice. Although most variables did not display significant variations, we observed a progressive increase in stage IV BC over this period. Our data showed that tumour stage III/IV or HER2-enriched subtype tumours were associated with poorer prognosis. In contrast, we found that patients diagnosed by mammography had better overall survival. We speculate that better screenings and more sensitive imaging could explain the unexpected rise in stage IV cases. Our results support mammography screenings as an effective measure to reduce BC-related mortality.


Hospital fundamentals.
Under the current system, orthopaedic trauma surgeons must work in some form of hospital setting as our primary service involves treatment of the trauma patient. We must not forget that just as a trauma center cannot exist without our services, we cannot function without their support. As a result, a clear understanding of the balance between physicians and hospitals is paramount. Historical perspective enables physicians and hospital personnel alike to understand the evolution of hospital-physician relationship. This process should be understood upon completion of this chapter. The relationship between physicians and hospitals is becoming increasingly complex and multiple forms of integration exist such as joint ventures, gain sharing, and co-management agreements. For the surgeon to negotiate well, an understanding of hospital governance and the role of the orthopaedic traumatologist is vital to success. An understanding of the value provided by the traumatologist includes all aspects of care including efficiency, availability, cost effectiveness, and research activities. To create effective and sustainable healthcare institutions, physicians and hospitals must be aligned over a sustained period of time. Unfortunately, external forces have eroded the historical basis for the working relationship between physicians and hospitals. Increased competition and reimbursement cuts, coupled with the increasing demands for quality, efficiency, and coordination and the payment changes outlined in healthcare reform, have left many organizations wondering how to best rebuild the relationship. The principal goal for the physician when partnering with a hospital or healthcare entity is to establish a sustainable model of service line management that protects or advances the physician's ability to make impactful improvements in quality of patient care, decreases in healthcare costs, and improvements in process efficiency through evidence-based practices and protocols.


The antipsychotics clozapine and olanzapine increase plasma glucose and corticosterone levels in rats: comparison with aripiprazole, ziprasidone, bifeprunox and F15063.
Several novel antipsychotics activate serotonin 5-HT1A receptors as well as antagonising dopamine D2/3 receptors. Such a pharmacological profile is associated with a lowered liability to produce extrapyramidal side effects and enhanced efficacy in treating negative and cognitive symptoms of schizophrenia. However, 5-HT1A receptor agonists increase plasma corticosterone and many antipsychotics disturb the regulation of glucose. Here, we compared the influence on plasma glucose and corticosterone of acute treatments with 'new generation' antipsychotics which target dopamine D2/3 receptors and 5-HT1A receptors, with that of atypical antipsychotics, and with haloperidol. Olanzapine and clozapine, antipsychotics that are known to produce weight gain and diabetes in humans, both at 10 mg/kg p.o., substantially increased plasma glucose (from 0.8 to 1.7 g/l) at 1 h after administration, an effect that returned to control levels after 4 h. In comparison, F15063 (40 mg/kg p.o.) was without effect at any time point. Olanzapine and clozapine dose-dependently increased plasma glucose concentrations as did SLV313 and SSR181507. Haloperidol and risperidone had modest effects whereas aripiprazole, ziprasidone and bifeprunox, antipsychotics that are not associated with metabolic dysfunction in humans, and F15063 had little or no influence on plasma glucose. The same general pattern of response was found for plasma corticosterone levels. The present data provide the first comparative study of conventional, atypical and 'new generation' antipsychotics on glucose and corticosterone levels in rats. A variety of mechanisms likely underlie the hyperglycemia and corticosterone release observed with clozapine and olanzapine, whilst the balance of dopamine D2/3/5-HT1A interaction may contribute to the less favourable impact of SLV313 and SSR181507 compared with that of bifeprunox and F15063.


Validation of real-time PCR assays for bioforensic detection of model plant pathogens.
The U.S. agricultural sector is vulnerable to intentionally introduced microbial threats because of its wide and open distribution and economic importance. To investigate such events, forensically valid assays for plant pathogen detection are needed. In this work, real-time PCR assays were developed for three model plant pathogens: Pseudomonas syringae pathovar tomato, Xylella fastidiosa, and Wheat streak mosaic virus. Validation included determination of the linearity and range, limit of detection, sensitivity, specificity, and exclusivity of each assay. Additionally, positive control plasmids, distinguishable from native signature by restriction enzyme digestion, were developed to support forensic application of the assays. Each assay displayed linear amplification of target nucleic acid, detected 100 fg or less of target nucleic acid, and was specific to its target pathogen. Results obtained with these model pathogens provide the framework for development and validation of similar assays for other plant pathogens of high consequence.


Phosphorylation of four acyclic guanosine analogs by herpes simplex virus type 2 thymidine kinase.
Four acyclic guanosine analogs, the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine, 9-(4-hydroxybutyl)guanine, and acyclovir were compared in enzyme kinetic experiments, using purified herpes simplex virus type 2 thymidine kinase. All four analogs showed competitive patterns of inhibition in the phosphorylation of thymidine by the viral thymidine kinase, but different affinities and relative rates of phosphorylation were observed.


Infection and disease caused by environmental mycobacteria.
Many species of mycobacteria that normally live as environmental saprophytes, the environmental mycobacteria (EM), are opportunist causes of disease in humans and animals. Many, but not all, cases are associated with some form of immune deficiency. An increasing number of species and clinical presentations are being described, and advances are being made in the understanding of the underlying predisposing factors. In recent years, four aspects of EM disease have become particularly relevant to human health: (1) the high prevalence of EM disease in patients with AIDS; (2) the emergence of Buruli ulcer, an ulcerative skin disease caused by Mycobacterium ulcerans, as the third most prevalent mycobacterial disease; (3) the effect of infection by EM on the immune responses to BCG vaccination and on the course and outcome of tuberculosis and leprosy; (4) the controversy over the involvement of mycobacteria, notably M. avium subspecies paratuberculosis, in human inflammatory bowel disease. These aspects change the status of EM from mere curiosities to important direct, indirect, and putative causes of serious and increasingly common human disease.


Etiology, microbiological isolates, and antibiotic susceptibilities in culture-proven pediatric endophthalmitis: a 9-year review.
To analyze the etiology, microbiological isolates, and antibiotic susceptibilities of endophthalmitis in pediatric patients. Patients aged < 18 years with culture-positive endophthalmitis in Zhongshan Ophthalmic Center between January 2010 and December 2018 were included retrospectively. A total of 127 patients (127 eyes) were included, and 108 (85%) had posttraumatic endophthalmitis. Streptococcus (21.4%), coagulase-negative Staphylococcus (14.5%), Aspergillus (6.9%), and Bacillus cereus (5.3%) were the common organisms. The proportion of Streptococcus decreased with age (40.0% in 0-3 years, 16.3% in 4-12 years, and 6.3% in 13-17 years), while coagulase-negative Staphylococcus increased from 5.7% to 18.8%. Overall, fluoroquinolones achieved the highest antibiotic susceptibility rate (> 95%), while the susceptibility of isolated bacteria to tobramycin and cefazolin was only 60.2% and 59.4%, respectively. The susceptibility rates of Gram-positive cocci to cephalosporins were nearly 90%. For Gram-negative bacilli, susceptibility to neomycin was 91.3%. Trauma was the main etiology for pediatric endophthalmitis. Although Streptococcus was the most prevalent organism in general, the dominant pathogen varied with age, which merits clinical attention. Fluoroquinolones showed the highest antibiotic efficacy; however, commonly used antibiotics tobramycin and cefazolin showed relatively low antibiotic susceptibility. Thus, antibiotic resistance in pediatric populations merits clinical attention.


Complement receptor expression by neoplastic and normal human cells.
Complement receptor (CR) expression in cell lines derived from Burkitt's lymphoma (BL), Epstein Barr virus-transformed cord blood lymphocytes (CB), and peripheral lymphocytes from patients with infectious mononucleosis (IM) was examined. Red cell intermediates bearing various densities of C4b, C3b, C3bi, or C3d were tested for rosette formation with the cell lines. In addition, a series of studies was performed under conditions that precluded the cleavage of cellbound C3b by Factor I (C3bINA). These conditions did not alter rosetting by the cells that were tested. RAJI cells rosetted with EAC3bi greater than EAC3d greater than EAC3b, but not with EAC4b. EAC3b/RAJI rosette formation required much greater quantities of C3b bound to red cells than did CB and IM lines, which unlike RAJI, also bound EAC4b. All of the BL lines failed to bind EAC4b even at a C4b density of 50,000 molecules/cell, but several lines did form rosettes with EAC3b, and most formed rosettes with EAC3bi and EAC3d. Fluid phase C3b blocked RAJI/EAC3b rosetting while having little effect on RAJI/EAC3bi rosette activity. Moreover, fluid phase C3b, as well as C4b, blocked RAJI/EAC3b rosettes more effectively than CB/EAC3b rosettes. The results indicate that the RAJI cell line has a receptor for C3b, with characteristics that differ markedly from the C3b receptor of cell lines derived from CB lymphocytes and of lymphoblastoid cell lines derived from patients with IM. This receptor is capable of interacting with soluble but not cellbound C4b. In these studies, rosette formation was examined under various ionic conditions. RAJI/EAC3b rosette formation was severely reduced as ionic strength was increased, whereas RAJI/EAC3bi binding was only moderately decreased at physiologic ionic strength. In striking contrast, EAC3bi binding to monocytes, PMN, and human erythrocytes was markedly reduced as ionic strength increased, but EAC3b binding to these cells was less sensitive to changes in ionic strength. Under conditions of physiologic ionic strength, the C3bi receptor of phagocytic cells may be at a functional disadvantage in the binding of C3bi-coated particles. This may have major physiologic implications.


Carboxyl-proximal regions of reovirus nonstructural protein muNS necessary and sufficient for forming factory-like inclusions.
Mammalian orthoreoviruses are believed to replicate in distinctive, cytoplasmic inclusion bodies, commonly called viral factories or viroplasms. The viral nonstructural protein muNS has been implicated in forming the matrix of these structures, as well as in recruiting other components to them for putative roles in genome replication and particle assembly. In this study, we sought to identify the regions of muNS that are involved in forming factory-like inclusions in transfected cells in the absence of infection or other viral proteins. Sequences in the carboxyl-terminal one-third of the 721-residue muNS protein were linked to this activity. Deletion of as few as eight residues from the carboxyl terminus of muNS resulted in loss of inclusion formation, suggesting that some portion of these residues is required for the phenotype. A region spanning residues 471 to 721 of muNS was the smallest one shown to be sufficient for forming factory-like inclusions. The region from positions 471 to 721 (471-721 region) includes both of two previously predicted coiled-coil segments in muNS, suggesting that one or both of these segments may also be required for inclusion formation. Deletion of the more amino-terminal one of the two predicted coiled-coil segments from the 471-721 region resulted in loss of the phenotype, although replacement of this segment with Aequorea victoria green fluorescent protein, which is known to weakly dimerize, largely restored inclusion formation. Sequences between the two predicted coiled-coil segments were also required for forming factory-like inclusions, and mutation of either one His residue (His570) or one Cys residue (Cys572) within these sequences disrupted the phenotype. The His and Cys residues are part of a small consensus motif that is conserved across muNS homologs from avian orthoreoviruses and aquareoviruses, suggesting this motif may have a common function in these related viruses. The inclusion-forming 471-721 region of muNS was shown to provide a useful platform for the presentation of peptides for studies of protein-protein association through colocalization to factory-like inclusions in transfected cells.


Coherence of subsequent supercontinuum pulses generated in tapered fibers in the femtosecond regime.
We measure the degree of coherence of supercontinua generated in tapered fibers by subsequent fs pulses. By means of interference experiments we study its dependence on the input pulse duration and power. We also present numerical simulations that allow us to explain the experimental observations which show a decreasing degree of coherence with increasing input power. We attribute this loss of coherence to phase noise due to the cross-phase modulation by several solitons with randomly varying parameters due to quantum noise.


Convergent evolution in a large cross-cultural database of musical scales.
Scales, sets of discrete pitches that form the basis of melodies, are thought to be one of the most universal hallmarks of music. But we know relatively little about cross-cultural diversity of scales or how they evolved. To remedy this, we assemble a cross-cultural database (Database of Musical Scales: DaMuSc) of scale data, collected over the past century by various ethnomusicologists. Statistical analyses of the data highlight that certain intervals (e.g., the octave, fifth, second) are used frequently across cultures. Despite some diversity among scales, it is the similarities across societies which are most striking: step intervals are restricted to 100-400 cents; most scales are found close to equidistant 5- and 7-note scales. We discuss potential mechanisms of variation and selection in the evolution of scales, and how the assembled data may be used to examine the root causes of convergent evolution.


A Bayesian analysis of colonic crypt structure and coordinated response to carcinogen exposure incorporating missing crypts.
This paper is concerned with modeling the architecture of colonic crypts and the implications of this modeling for understanding possible coordinated response of carcinogen-induced DNA damage between various regions of the colon. The methods we develop to address these two issues are applied to a particular important example in colon carcinogenesis. We cast the problem as an unusual and not previously studied hierarchical mixed-effects model characterized by completely missing covariates in units at a structurally base level, except for some randomly selected units. Information concerning the missing covariates is available through certain known ordering constraints and surrogate measures. Our methods use Bayesian machinery. We exploit the biological structure of this problem to generate the missing covariates simultaneously and efficiently at the base levels, as opposed to the naive practice of generating units at the base levels one-at-a-time with Metropolis-Hastings steps. We apply our methods to show that different regions of the colon have different architectures, and to estimate an important but non-standard function that measures the interrelationship of DNA damage mechanisms in different regions of the colon.


Modified natural diatomite and its enhanced immobilization of lead, copper and cadmium in simulated contaminated soils.
Natural diatomite was modified through facile acid treatment and ultrasonication, which increased its electronegativity, and the pore volume and surface area achieved to 0.211 cm(3) g(-1) and 76.9 m(2) g(-1), respectively. Modified diatomite was investigated to immobilize the potential toxic elements (PTEs) of Pb, Cu and Cd in simulated contaminated soil comparing to natural diatomite. When incubated with contaminated soils at rates of 2.5% and 5.0% by weight for 90 days, modified diatomite was more effective in immobilizing Pb, Cu and Cd than natural diatomite. After treated with 5.0% modified diatomite for 90 days, the contaminated soils showed 69.7%, 49.7% and 23.7% reductions in Pb, Cu and Cd concentrations after 0.01 M CaCl2 extraction, respectively. The concentrations of Pb, Cu and Cd were reduced by 66.7%, 47.2% and 33.1% in the leaching procedure, respectively. The surface complexation played an important role in the immobilization of PTEs in soils. The decreased extractable metal content of soil was accompanied by improved microbial activity which significantly increased (P<0.05) in 5.0% modified diatomite-amended soils. These results suggested that modified diatomite with micro/nanostructured characteristics increased the immobilization of PTEs in contaminated soil and had great potential as green and low-cost amendments.


Physical activity in postdeployment Operation Iraqi Freedom/Operation Enduring Freedom veterans using Department of Veterans Affairs services.
Veteran activity levels may decrease between Active Duty and postdeployment. We examined attitudes and changes in self-reported activities between the two in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans using Department of Veterans Affairs (VA) services. We conducted an online cross-sectional survey (June-August 2008) of postdeployment OIF/OEF veterans registered with the VA Ann Arbor Healthcare System, Ann Arbor, Michigan. Descriptive statistics summarized demographic data and attitudes, while regression analyses compared physical activities during Active Duty with physical activities postdeployment. Participants (n = 319, 15.6% response rate) reported that they believe staying physically fit is important, they worry about gaining weight, and they believe exercise will keep them healthy (77%, 72%, and 90% agree or strongly agree, respectively). Running (30.0%), Exercise with Gym Equipment (21.5%), Occupational Activities (14.9%), and Walking (13.0%) were the most frequently reported Active Duty physical activities. The most frequently reported postdeployment physical activities included Walking (21.1%), Running (18.5%), and Exercise with Gym Equipment (17.9%). Health problems (39%) and chronic pain (52%) were common barriers to physical activity. Postdeployment OIF/OEF veterans using the VA believe physical activity is beneficial, yet many report health problems and/or chronic pain that makes exercise difficult. Physical activity promotes health, and strategies are needed to facilitate physical activity in this population.


Hispanic children and overweight: causes and interventions.
The incidence and prevalence of overweight is increasing to alarming rates in children and adolescents in the United States. Hispanic children are one of the highest risk groups for overweight. Many different factors are positively correlated with childhood overweight in Hispanics: lower socioeconomic status, lacking health insurance or being under-insured, poor diet, decreased physical activity, overweight status of parents, mother's perception of overweight, and degree of acculturation. Pediatric nurses are in a pivotal position to assist in curtailing the epidemic. Various evidence-based practices to prevent and treat pediatric overweight are discussed with recommendations to intervene, particularly with Hispanic youth.


Association between PCV13 pneumococcal vaccination and risk of hospital admissions due to pneumonia or sepsis among patients with haematological malignancies: a single-centre retrospective cohort study in Israel.
Patients with haematological malignancies receiving immunosuppressive therapy are at highest risk of invasive pneumococcal disease. Our goal was to investigate whether vaccination of haematological patients with pneumococcal 13-valent conjugated vaccine (PCV13) prior to therapy initiation is associated with decreased hospital admissions due to pneumonia or sepsis within 12 months. A longitudinal retrospective cohort study was conducted at the haematology unit of Carmel Medical Center, Israel. Information on adult patients (>18 years) who were diagnosed between 1 January 2009 and 30 December 2019 with haematological malignancies and received immunosuppressive therapy was retrieved from the electronic health records. Patients with haematological malignancies who received the PCV13 vaccination during or after initiation of the immunosuppressive therapy were excluded from the study. A multivariate logistic regression model was performed to determine whether PCV13 vaccination is associated with fewer hospital admissions due to pneumonia or sepsis. The cohort included 616 patients, of which 418 (67%) patients were not vaccinated and 198 (33%) were vaccinated. Within 12 months, 15.1% (n=63) of non-vaccinated patients compared with only 7.1% (n=14) of the vaccinated patients were hospitalised due to pneumonia or sepsis. The logistic regression analysis demonstrated that receiving PCV13 vaccination is associated with 45% (OR=0.45, 95% CI: 0.246 to 0.839, p=0.012) reduced odds of being hospitalised due to pneumonia or sepsis in patients with haematological malignancies receiving immunosuppressive therapy. This is the first observational study to demonstrate the association between PCV13 vaccination and hospital admissions in patients with haematological malignancies receiving immunosuppressive therapy. Patients receiving PCV13 vaccination before immunosuppressive therapy initiation had significantly reduced odds of hospitalisation due to pneumonia or sepsis compared with non-PCV13-vaccinated patients.


Egg White as a Quality Control in Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI).
The strength of MALDI-MSI is to analyze and visualize spatial intensities of molecular features from an intact tissue. The distribution of the intensities can then be visualized within a single tissue section or compared in between sections, acquired consecutively. This method can be reliably used to reveal physiological structures and has the potential to identify molecular details, which correlate with biological outcomes. MALDI-MSI implementation in clinical laboratories requires the ability to ensure method quality and validation to meet diagnostic expectations. To be able to get consistent qualitative and quantitative results, standardized sample preparation and data acquisition are of highest priority. We have previously shown that the deposition of internal standards onto the tissue section during sample preparation can be used to improve the mass accuracy of monitored m/z features across the sample. Here, we present the use of external and internal controls for the quality check of sample preparation and data acquisition, which is particularly relevant when either many spectra are acquired during a single MALDI-MSI experiment or data from independent experiments are processed together. To monitor detector performance and sample preparation, we use egg white as an external control for peptide and N-glycan MALDI-MSI throughout the experiment. We have also identified endogenous peptides from cytoskeletal proteins, which can be reliably monitored in gynecological tissue samples. Lastly, we summarize our standard quality control workflow designed to produce reliable and comparable MALDI-MSI data from single sections and tissue microarrays (TMAs).


Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.
The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.


Characterization of zinc-binding proteins of plasma in familial hyperzincemia.
Plasmas from three brothers (aged 35 to 45) with chronic hyperzincemia (325 to 525 micrograms/dl Zn) were analyzed and compared with pooled control plasma (104 microgram/dl Zn). The levels of copper, iron, total protein, albumin, and amino acids were similar in normal and hyperzincemic plasmas. Distribution of zinc among plasma components was determined chromatographically. Zinc eluted quantitatively in two distinct peaks from Sephadex G-100 gel filtration resin. The amount of the metal in fractions containing species larger than 100,000 molecular weight (peak I) was similar (35 to 45 micrograms/dl Zn) in normal and hyperzincemic plasmas. The additional complement of zinc in hyperzincemic plasma was localized within fractions containing zinc-binding proteins such as albumin, transferrin and HRG. That zinc was not associated with transferrin was determined by Affi-Gel affinity chromatography. The amounts of HRG in hyperzincemic plasmas were similar to or below those in control plasma. Zinc and albumin were selectively retained by anti-human albumin IgG coupled to protein A-Sepharose. In contrast, anti-human HRG IgG coupled to CM Bio-Gel A failed to bind plasma zinc. The findings indicate that (1) most available, protein-associated zinc in normal plasma is bound to albumin and (2) the additional complement of zinc in familial hyperzincemic plasma is associated with albumin. The biochemical basis for the enhanced binding of zinc by albumin in hyperzincemic plasma is unknown.


A critical ethnographic approach to facilitating cultural shift in midwifery.
to improve understanding of local midwifery morale, inform development and reorganisation of a maternity unit, and enhance midwifery involvement in strategic planning. a randomised stratified sample of 20 midwives working in a UK National Health Service (NHS) hospital and its surrounding community area. within a critical ethnographic framework, focus groups were tape-recorded and transcribed, and analysed using a thematic content analysis approach. key areas affecting midwifery morale were identified, in particular staffing levels, working relationships and organisational issues. One year later, despite many changes having taken place, midwifery morale was still low but participants were more politically analytical of, and actively involved in changing their situation. The findings of the study indicate that there are complex and long-standing cultural inhibitions to the effective development of midwifery care but, if these are made explicit through a planned collaborative process, such as in this study, a process of cultural shift can be seen to begin. focus groups can be a useful tool in moving midwifery culture forward within a local context.


Organ-specific distribution of AP-1 in AP-1 luciferase transgenic mice during the maturation process.
Activator protein-1 (AP-1), a dimeric complex consisting of proteins encoded by the jun and fos gene families, is a transcription factor induced by a variety of signals including those eliciting proliferation, differentiation, and neoplastic transformation. Although AP-1 has been widely studied in the last decade, physiological levels of AP-1 in different tissues are unclear. In the present study, we analyzed AP-1 activity in several organs (liver, kidney, brain, lung, spleen, heart, skin) of AP-1-luciferase transgenic mice of various ages. Results of these studies indicate that the level of AP-1 in young mice is much higher than that in older mice, and, second, that the skin contains considerably higher levels of AP-1 than other organs. The level of phosphorylated extracellular signal-regulated protein kinase (ERK) in skin was higher in 1- and 2-day-old mice than in mice of other ages. In addition, phosphorylated p38 kinase was high in 2-day-old and 1-wk-old mice, but phosphorylated c-Jun NH(2)-terminal kinase was not detected at any age. AP-1 activity and level of phosphorylated ERKs declined with maturation. These results imply that AP-1 activity mediated through an ERKs-dependent pathway may be involved in skin development.


A promoter that acquired p53 responsiveness during primate evolution.
The tumor suppressor p53 activates the transcription of human PIG3 through direct interaction with a polymorphic microsatellite sequence, (TGYCC)(n). Here, the evolution of this p53-responsive element was recapitulated. Comparison between primate species revealed that the PIG3 promoter acquired this sequence element in its full length only in Hominoidea (apes and humans), whereas the number of TGYCC repeats is far lower in monkeys. Accordingly, only the PIG3 promoters from Hominoidea respond efficiently to p53, whereas those from monkeys respond poorly or not at all. In parallel, the PIG3 gene was strongly induced by p53 in human and chimpanzee cells but was unaffected by p53 in cells derived from a common marmoset monkey. Thus, a novel p53 target gene appeared as recently as during the evolution of primates. This suggests that mechanisms of tumor suppression are subject to ongoing evolution in humans and their closest relatives.


Expiratory loading improves cardiac output during exercise in heart failure.
The objective of this study was to investigate the effect of changes in expiratory intrathoracic pressure on stroke volume (SV) at rest and during moderate exercise in patients with heart failure versus healthy individuals. SV was obtained by echocardiography during spontaneous breathing and during expiratory loads of 5 and 10 cm H2O produced by a ventilator in 11 patients with heart failure (61 ± yr, ejection fraction: 32 ± 4%, New York Heart Association, 32% ± 4%; NYHA class I-II) and 11 age-matched healthy individuals at rest and during exercise at 60% of aerobic capacity on a semirecumbent cycle ergometer. At rest, expiratory loading did not change HR, SV index (SVI), or cardiac index (CI) in either group. During moderate exercise, expiratory loading increased SVI and CI in patients with heart failure but decreased SVI and CI in healthy individuals. There was a negative correlation between changes in gastric pressure and SVI (r = -0.51, P < 0.05) in healthy individuals, whereas there was a positive correlation between changes in gastric pressure accompanying expiratory loading and CI (r = 0.83, P < 0.01) in patients with heart failure. Expiratory loading during moderate exercise elicited increases in SVI and CI in patients with heart failure but decreased SVI and CI in healthy individuals. Improvements in cardiac function during submaximal exercise in patients with heart failure may be caused by a beneficial reduction in left ventricular preload.


Detection of suspected malignant patterns in three-dimensional magnetic resonance breast images.
In this article, a Boolean Neural Network (BNN) is used for the detection of suspected malignant regions in 3D breast magnetic resonance (MR) images. The BNN is characterized by fast learning and classification, guaranteed convergence, and simple, integer weight calculations. The BNN learning algorithm is incremental, which allows the addition and deletion of training patterns without unlearning those already learned. The incremental learning algorithm automatically reduces the training set and trains the network only with those examples estimated to be useful. The architecture is suitable for parallel hardware implementation using available Very Large Scale Integration (VLSI) technology. The BNN was trained by using a set of malignant, benign, and false-positive patterns, extracted by experts, from selected MR studies, by using an incremental learning algorithm. After training, the network was tested by means of a consistency checking test, cross validation techniques, and patterns from actual MR breast images. During the consistency test, the BNN was tested by using the same patterns used for training. The BNN classification accuracy in this case was 99.75%, proving the ability of the BNN to select useful patterns from the training set. Then, a leave one out cross-validation (LOOCV) test was done by using patterns from the training set and the classification accuracy was 90%. Next, an extended training set was created by shifting the original patterns in different directions. A cross-validation test was then performed by dividing the set of patterns into a training and a test set. Classification accuracy was compared to the nearest neighbor classifier. Results showed that the BNN achieved an average of 77% classification accuracy while requiring only 34% of the original training set. On the other hand, the nearest neighbor classifier achieved an accuracy of 57.9% while retaining the whole training set. Another test using actual MR slices different from the training set was done and results compared favorably to a radiologist's findings. Test results show the BNN's capability to detect suspected malignant regions in 3D MR images of the breast. The proposed BNN architecture can save the radiologist a great deal of time browsing MR slices searching for suspected malignancies.


Design of ratiometric emission probe with visible light excitation for determination of Ca2+ in living cells.
An organic salt as a fluorescent probe based on intramolecular charge transfer for Ca(2+) determination is developed. Ca(2+) can be detected by ratiometric emission at 490 and 594 nm with an excitation wavelength of 405 nm. This probe is highly selective for Ca(2+) over other divalent metal cations and displays a large Stokes shift of 189 nm that can avoid interference of the excitation light beam and autofluorescence of biological samples. The dissociation constant for Ca(2+) is 2.25 ± 0.47 μM and pertinent to Ca(2+) detection in cellular resting and dynamic states. The probe demonstrates its application in monitoring Ca(2+) in living cells under confocal microscopic imaging.


Changing nutrition care practices in hospital: a thematic analysis of hospital staff perspectives.
Many patients are admitted to hospital and are already malnourished. Gaps in practice have identified that care processes for these patients can be improved. Hospital staff, including management, needs to work towards optimizing nutrition care in hospitals to improve the prevention, detection and treatment of malnutrition. The objective of this study was to understand how staff members perceived and described the necessary ingredients to support change efforts required to improve nutrition care in their hospital. A qualitative study was conducted using purposive sampling techniques to recruit participants for focus groups (FG) (n = 11) and key informant interviews (n = 40) with a variety of hospital staff and management. Discussions based on a semi-structured schedule were conducted at five diverse hospitals from four provinces in Canada as part of the More-2-Eat implementation project. One researcher conducted 2-day site visits over a two-month period to complete all interviews and FGs. Interviews were transcribed verbatim while key points and quotes were taken from FGs. Transcripts were coded line-by-line with initial thematic analysis completed by the primary author. Other authors (n = 3) confirmed the themes by reviewing a subset of transcripts and the draft themes. Themes were then refined and further detailed. Member checking of site summaries was completed with site champions. Participants (n = 133) included nurses, physicians, food service workers, dietitians, and hospital management, among others. Discussion regarding ways to improve nutrition care in each specific site facilitated the thought process during FG and interviews. Five main themes were identified: building a reason to change; involving relevant people in the change process; embedding change into current practice; accounting for climate; and building strong relationships within the hospital team. Hospital staff need a reason to change their nutrition care practices and a significant change driver is perceived and experienced benefit to the patient. Participants described key ingredients to support successful change and specifically engaging the interdisciplinary team to effect sustainable improvements in nutrition care. Retrospectively registered ClinicalTrials.gov Identifier: NCT02800304 , June 7, 2016.


Analysis of FMRP mRNA target datasets reveals highly associated mRNAs mediated by G-quadruplex structures formed via clustered WGGA sequences.
Fragile X syndrome, a common cause of intellectual disability and a well-known cause of autism spectrum disorder, is the result of loss or dysfunction of fragile X mental retardation protein (FMRP), a highly selective RNA-binding protein and translation regulator. A major research priority has been the identification of the mRNA targets of FMRP, particularly as recent studies suggest an excess of FMRP targets among genes implicated in idiopathic autism and schizophrenia. Several large-scale studies have attempted to identify mRNAs bound by FMRP through several methods, each generating a list of putative target genes, leading to distinct hypotheses by which FMRP recognizes its targets; namely, by RNA structure or sequence. However, no in depth analyses have been performed to identify the level of consensus among the studies. Here, we analyze four large FMRP target datasets to generate high-confidence consensus lists, and examine all datasets for sequence elements within the target RNAs to validate reported FMRP binding motifs (GACR, ACUK and WGGA). We found GACR to be highly enriched in FMRP datasets, while ACUK was not. The WGGA pattern was modestly enriched in several, but not all datasets. The previous association between FMRP and G-quadruplexes prompted the analysis of the distribution of WGGA in the target genes. Consistent with the requirements for G-quadruplex formation, we observed highly clustered WGGA motifs in FMRP targets compared with other genes, implicating both RNA structure and sequence in the recognition motif of FMRP. In addition, we generate a list of the top 40 FMRP targets associated with FXS-related phenotypes.


Comparative Population Genetic Structure of the Endangered Southern Brown Bandicoot, Isoodon obesulus, in Fragmented Landscapes of Southern Australia.
Genetic connectivity is a key factor for maintaining the persistence of populations in fragmented landscapes. In highly modified landscapes such us peri-urban areas, organisms' dispersal among fragmented habitat patches can be reduced due to the surrounding matrix, leading to subsequent decreased gene flow and increased potential extinction risk in isolated sub-populations. However, few studies have compared within species how dispersal/gene flow varies between regions and among different forms of matrix that might be encountered. In the current study, we investigated gene flow and dispersal in an endangered marsupial, the southern brown bandicoot (Isoodon obesulus) in a heavily modified peri-urban landscape in South Australia, Australia. We used 14 microsatellite markers to genotype 254 individuals which were sampled from 15 sites. Analyses revealed significant genetic structure. Our analyses also indicated that dispersal was mostly limited to neighbouring sites. Comparisons of these results with analyses of a different population of the same species revealed that gene flow/dispersal was more limited in this peri-urban landscape than in a pine plantation landscape approximately 400 km to the south-east. These findings increase our understanding of how the nature of fragmentation can lead to profound differences in levels of genetic connectivity among populations of the same species.


Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking.
Excessive consumption of alcohol is a major problem in the United States and abroad. Despite many years of study, it is unclear why some individuals drink alcohol excessively while others do not. It has been postulated that either lower or greater acute responses to alcohol, or both, depending on the limb of the breath alcohol concentration curve, contribute to propensity for alcohol misuse. To prospectively assess the relationship of acute alcohol responses to future binge drinking. Within-subject, double-blind, placebo-controlled, multidose laboratory alcohol challenge study with intensive follow-up. Each participant completed 3 randomized sessions examining responses to a high (0.8 g/kg) and low (0.4 g/kg) alcohol dose and placebo, followed by quarterly assessments for 2 years examining drinking behaviors and alcohol diagnoses. Participants recruited from the community. High-risk heavy social drinkers aged 21 to 35 years who habitually engage in weekly binge drinking (n = 104) and light drinker controls (n = 86). We conducted 570 laboratory sessions with a subsequent 99.1% follow-up (1506 of 1520). Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, cortisol response, Timeline Follow-Back, Drinker Inventory of Consequences-Recent, and DSM-IV alcohol abuse and dependence. Alcohol produced greater stimulant and rewarding (liking and wanting) responses and lower sedative and cortisol responses in heavy vs light drinkers. Among the heavy drinkers, greater positive effects and lower sedative effects after alcohol consumption predicted increased binge drinking frequency during follow-up. In turn, greater frequency of binge drinking during follow-up was associated with greater likelihood of meeting diagnostic criteria for alcohol abuse and dependence. The widely held low level response theory and differentiator model should be revised: in high-risk drinkers, stimulant and rewarding alcohol responses even at peak breath alcohol concentrations are important predictors of future alcohol problems. clinicaltrials.gov Identifier: NCT00961792.


Principle and design of clinical efficacy observation of extracorporeal cardiac shock wave therapy for patients with myocardial ischemia-reperfusion injury: A prospective randomized controlled trial protocol.
Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life threatening event with a poor prognosis due to myocardial ischemia/reperfusion injury despite coronary revascularization. Extracorporeal cardiac shock wave (ECSW) is a safe, effective and non-invasive new method for the treatment of cardiovascular diseases. The current results show that extracorporeal cardiac shock wave provides a new treatment option for patients with severe and advanced coronary heart disease. However, there are relatively few clinical studies on the application of in vitro cardiac shock waves in patients with myocardial ischemia-reperfusion injury. We hypothesized that extracorporeal cardiac shock therapy would also be effective in reducing clinical endpoints in patients with STEMI reperfusion. This study is order to provide a new therapeutic method for patients with myocardial ischemia-reperfusion injury and reveal the possible mechanism of ECSW for ischemia-reperfusion injury. CEECSWIIRI is a single-center, prospective randomized controlled trial that plans to enroll 102 eligible patients with acute ST-segment elevation myocardial infarction reperfusion. Eligible patients with STEMI reperfusion will be randomly divided into external cardiac shock therapy (ECSW) trial group and blank control group. The blank control group will receive optimal drug therapy, and the experimental group will receive optimal drug therapy combined with ECSW. The shock wave treatment plan will be 3-month therapy, specifically 1 week of treatment per month, 3 weeks of rest, 3 times of ECSW in each treatment week, respectively on the first day, the third day and the fifth day of the treatment week, lasting for 3 months and follow-up for 2 years. The primary endpoint will be to assess the 2-year improvement in all-cause death, re-hospitalization due to cardiovascular disease, major unintentional cerebrovascular events, including cardiogenic death, myocardial infarction, heart failure, arrhythmia, emergency coronary revascularization, and stroke in patients with STEMI reperfusion. Secondary endpoints will include improvements in angina pectoris, quality of life, cardiac structure and function, coronary microcirculation, and endothelial progenitor cell-derived miR-140-3p in relation to survival outcomes. ClinicalTrial.gov.org PRS:NCT05624203; Date of registration: November 12, 2022.


Corticosteroids in IgA Nephropathy: A Retrospective Analysis from the VALIGA Study.
Current guidelines suggest treatment with corticosteroids (CS) in IgA nephropathy (IgAN) when proteinuria is persistently ≥1 g/d despite 3-6 months of supportive care and when eGFR is >50 ml/min per 1.73 m(2). Whether the benefits of this treatment extend to patients with an eGFR≤50 ml/min per 1.73 m(2), other levels of proteinuria, or different renal pathologic lesions remains unknown. We retrospectively studied 1147 patients with IgAN from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification and medication used, with details of duration but not dosing. Overall, 46% of patients received immunosuppression, of which 98% received CS. Treated individuals presented with greater clinical and pathologic risk factors of progression. They also received more antihypertensive medication, and a greater proportion received renin angiotensin system blockade (RASB) compared with individuals without immunosuppressive therapy. Immunosuppression was associated with a significant reduction in proteinuria, a slower rate of renal function decline, and greater renal survival. Using a propensity score, we matched 184 subjects who received CS and RASB to 184 patients with a similar risk profile of progression who received only RASB. Within this group, CS reduced proteinuria and the rate of renal function decline and increased renal survival. These benefits extended to those with an eGFR≤50 ml/min per 1.73 m(2), and the benefits increased proportionally with the level of proteinuria. Thus, CS reduced the risk of progression regardless of initial eGFR and in direct proportion to the extent of proteinuria in this cohort.


Hypogonadal men with psoriasis benefit from long-term testosterone replacement therapy - a series of 15 case reports.
Psoriasis is increasingly recognised as a skin disease with far-reaching systemic effects, associated with a high prevalence of comorbid disease such as cardiometabolic dysfunction, shifting the focus from a single organ disease confined to the skin to a systemic inflammatory condition. Chronic and systemic inflammation plays a major role in the development of these diseases, and there are striking similarities between the molecular and inflammatory pathways in psoriasis and atherosclerosis. In a single-centre, cumulative, prospective registry study of 347 hypogonadal men (total testosterone ≤12.1 nmol l(-1) ), fifteen men with psoriasis could be studied. Upon testosterone administration, the skin disease improved considerably. Scores on the Psoriasis Area and Severity Index and Physician Global Assessment for Psoriasis showed significant improvement for the first 24 months. Thereafter, these improvements were sustained. Upon testosterone treatment, C-reactive protein declined significantly. There were significant improvements of obesity and of lipid profiles. Adipose tissue is now regarded as a source of inflammatory factors. These preliminary results deserve to be studied in a specifically designed study to investigate the effects of testosterone on psoriasis and its associated immunopathology.


Respiratory and cardiovascular effects of prostaglandins in the conscious guinea pig.
A technique to assess respiratory and cardiovascular effects of prostaglandins (PGs) in conscious guinea pigs was developed. Animals were placed in a plethysmograph and tidal volume, airflow, and heart rate were recorded. In addition, blood pressure and/or pleural pressure were obtained. Some experiments involved the use of a pulmonary calculator that processed the appropriate pulmonary signal and provided on-line readout of dynamic compliance and airway resistance. Aerosolized antagonists were evaluated for their ability to block responses to aerosolized histamine. We found the relative antagonistic potencies of PGE1, PGE2, isoproterenol, and salbutamol to be 5.5, 2.3, 1 and 0.2, respectively. Aerosolized PGE1 and PGE2 but not PGF2alpha given prior to histamine caused decreases in tidal volume, airflow and heart rate. These effects were not seen in animals that were prepared for measurements involving invasive surgical techniques. The aerosolized PGE2 induced tidal volume changes were not prevented by pretreatment with salbutamol, chlorpheniramine, atropine or hexamethonium, though the latter two drugs inhibited the fall in heart rate. We suggest that the bradycardia following aerosolized PGE2 administration may originate from airway irritant receptors. The results validate use of our methods for the assessment of responses to bronchoactive agents under physiological conditions.


Phenotypic differences in cardiovascular regulation in inbred rat models of aerobic capacity.
The Dark Aouti (DA) inbred strain of rats has superior aerobic treadmill running capacity compared with the Copenhagen (COP) strain of inbred rats. This difference in aerobic capacity provides a model to explore the genetic basis of variation in this trait. The present study evaluated intermediate phenotypic differences between 10 male COP inbred rats and 10 male DA inbred rats that might contribute to the difference in aerobic capacity between the strains. Five autonomically regulated cardiovascular variables were evaluated during rest or exercise by measuring the response to autonomic antagonists. The DA rat had enhanced autonomic function for the regulation of peripheral blood flow and cardiac output. Specifically, at rest the DA rats had significantly more sympathetic (123 +/- 8 vs. 99 +/- 7 beats/min) and parasympathetic (35 +/- 5 vs. 12 +/- 3 beats/min) tonus for heart rate control and more sympathetic support of blood pressure (70 +/- 7 vs. 38 +/- 6 mmHg) compared with the COP rats. During three graded levels of treadmill exercise the DA rats had higher blood pressures (16% on average) and higher heart rates (4% on average) relative to the COP rats. In addition, the DA rats had a 27% greater heart weight-to-body weight ratio compared with the COP strain of rats (3.63 +/- 0.08 vs. 2.85 +/- 0.07 g/kg). All five of these intermediate phenotypes could participate as variables causative of the difference in treadmill running capacity between the DA and COP strains of rats.


Brain grafting as a treatment for Parkinson's disease.
Parkinson's disease is an illness with neuropathological and neuroanatomical abnormalities in many areas of the central nervous system. Some clinical manifestations of this illness are correlated with pathological changes in the substantia nigra and with a loss of dopamine in the nigra and striatum. The most effective pharmacological treatments have used agents that either replace the lost dopamine or act as agonists on dopamine receptors. Recent studies in animal models of Parkinson's disease demonstrate that the loss of dopamine and many clinical manifestations of dopamine reduction can be reversed by transplantation of fetal dopamine-containing cells to specific dopamine-depleted areas of the brain. Long term viability of these transplants has also been demonstrated. The author suggests that the transplantation of dopamine neurons, even across species barriers, is a reasonable consideration for the treatment of human Parkinson's disease. This article reviews in detail the results of recent experiments and how the experience in these models might be utilized in determining a transplantation strategy for the treatment of specific clinical aspects of this illness.


Complexation of the triphosphate anion: tuning the structure of cyclen based macrotricycles with 1,3-dimethylbenzene and 2,6-dimethylpyridine linkers. A potentiometric and NMR study.
The host-guest interaction between orthophosphate, pyrophosphate and triphosphate anions and three cyclen-based macrotricyclic ligands was investigated by potentiometric measurements and NMR spectroscopy. The ligands differ from one another by the nature of their spacers, which are 1,3-dimethylbenzene (TMC), 2,6-dimethylpyridine (TPyC) or a combination of the two (TMPyC). In aqueous solution, each ligand gave protonated species that further formed ternary complexes after binding with anions; these complexes were analyzed as a result of hydrogen bond formation and coulombic attraction between the organic host and the inorganic guest. The equilibrium constants found for all the detected species are reported and the selectivity, illustrated with species distribution diagrams, is discussed. The results unambiguously showed that the ligand possessing a single supplementary anchoring site (the pyridinyl spacer) exhibited the greatest affinity for the phosphate species in a large p[H] range.


Quinidine-induced inhibition of transient outward current in cardiac muscle.
Quinidine is frequently used as a class I antiarrhythmic agent in the management of cardiac rhythm disturbances. It depresses the rapid initial depolarization of the action potential by blocking the sodium current, INa. In addition, quinidine increases the duration of the action potential and lengthens the refractory period. We have used a whole cell voltage-clamp technique to study the ionic mechanism underlying the lengthening of the action potential in single cells from the atrium and ventricle of the rabbit heart. Our data show that quinidine at therapeutic doses (3-10 microM) is a potent and selective inhibitor of a transient outward current, which controls the early repolarization of the action potential. In contrast, neither the calcium current, ICa, nor the time-independent background K+ current, IK1, is changed significantly by 10 microM quinidine. The reduction in the transient outward current can explain the lengthening of action potential and provides new insight into the mechanism of action of quinidine as an antiarrhythmic agent.


LIVE-PAINT allows super-resolution microscopy inside living cells using reversible peptide-protein interactions.
We present LIVE-PAINT, a new approach to super-resolution fluorescent imaging inside live cells. In LIVE-PAINT only a short peptide sequence is fused to the protein being studied, unlike conventional super-resolution methods, which rely on directly fusing the biomolecule of interest to a large fluorescent protein, organic fluorophore, or oligonucleotide. LIVE-PAINT works by observing the blinking of localized fluorescence as this peptide is reversibly bound by a protein that is fused to a fluorescent protein. We have demonstrated the effectiveness of LIVE-PAINT by imaging a number of different proteins inside live S. cerevisiae. Not only is LIVE-PAINT widely applicable, easily implemented, and the modifications minimally perturbing, but we also anticipate it will extend data acquisition times compared to those previously possible with methods that involve direct fusion to a fluorescent protein.


Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed-triple formulation) in intermittent antituberculous chemotherapy.
A study was carried out in six human volunteers, to assess the blood kinetics of isoniazid, rifampicin and pyrazinamide, administered in a fixed-triple combination intended for use in intermittent chemotherapy of tuberculosis. The formulation employed contained 125 mg of isoniazid (H), 100 mg of rifampicin (R) and 375 mg of pyrazinamide (Z) per tablet; six tablets were administered to every subject, giving a total dosage of 750 mg of isoniazid, 600 mg of rifampicin and 2,250 mg of pyrazinamide. In each subject, the same dose of each drug was administered individually in separate sessions and the results compared. The results indicated that, at the level of dose of the intermittent tablet, no negative interactions between the drugs were observed.


Consequences of intrauterine growth restriction for the kidney.
Low birth weight due to intrauterine growth restriction is associated with various diseases in adulthood, such as hypertension, cardiovascular disease, insulin resistance and end-stage renal disease. The purpose of this review is to describe the effects of intrauterine growth restriction on the kidney. Nephrogenesis requires a fine balance of many factors that can be disturbed by intrauterine growth restriction, leading to a low nephron endowment. The compensatory hyperfiltration in the remaining nephrons results in glomerular and systemic hypertension. Hyperfiltration is attributed to several factors, including the renin-angiotensin system (RAS), insulin-like growth factor (IGF-I) and nitric oxide. Data from human and animal studies are presented, and suggest a faltering IGF-I and an inhibited RAS in intrauterine growth restriction. Hyperfiltration makes the kidney more vulnerable during additional kidney disease, and is associated with glomerular damage and kidney failure in the long run. Animal studies have provided a possible therapy with blockage of the RAS at an early stage in order to prevent the compensatory glomerular hyperfiltration, but this is far from being applicable to humans. Research is needed to further unravel the effect of intrauterine growth restriction on the kidney.


Oral and oropharyngeal high-risk HPV prevalence, HIV status, and risk behaviours in a cohort of South African men who have sex with men.
Data lag is evident when observing studies focussing on human papillomavirus (HPV) prevalence in the head and neck of men who have sex with men (MSM) in Southern Africa. Sexual behaviours other than anal intercourse, and associated factors are similarly underreported. HPV vaccination has not yet commenced for this population group. One hundred and ninety-nine MSM were enrolled in this study. Participants completed a questionnaire followed by a clinical oral examination, and a rinse-and-gargle specimen in Thinprep® vials containing Preservcyt® solution was collected. Detection and genotyping for high-risk HPV were done by an automated system (Abbott® m2000sp). Six percent of MSM in this cohort had high-risk HPV present in the mouth/oropharynx. This cohort averages 29 years of age, more than half were unemployed (53.3%), and 66.8% were human immunodeficiency virus (HIV) seropositive. The most common sexual practice was anal sex (69.4%) followed by oral sex (28.6%), and by rimming (9.6%). A significant association between oral insertive sex and oral/oropharyngeal HPV status was demonstrated (p = 0.0038; phi coefficient = 0.20). An incidental but significant association between rimming and HIV status was found (p = 0.0046; phi coefficient = 0.19), and HIV seropositive participants had higher oral/oropharyngeal HPV presence. The HPV prevalence of 6% reported in this study is in alignment with global reports. The prevalence of oral/oropharyngeal HPV in this MSM cohort was influenced by sexual practices. MSM participants who practiced rimming appear to be at higher risk of HIV acquisition. Given the transmission routes of HPV in this vulnerable population, vaccination must be urgently studied as an intervention for prevention.


Effect of intermittent blood pressure elevation on the growth of experimental saccular aneurysms in the rat.
In this study we applied the technique described in the previous paper (see pp. 103-106 of previous issue (1991); 13(2)) to rats with experimental saccular aneurysms. We found that the mean sizes and some growth ratios of experimental aneurysms were significantly larger in the intermittent blood pressure elevation groups than in the control groups. The increase of growth ratios was proportional to the number of transient blood pressure elevations. The morphological structure of these saccular aneurysms showed that the regenerative processes in the aneurysm wall had obviously been interfered with in animals with intermittent blood pressure elevation. The effective mechanism of this influential factor is discussed.


Interleukin-11 inhibits NF-kappaB and AP-1 activation in islets and prevents diabetes induced with streptozotocin in mice.
This laboratory has reported that multiple low doses of streptozotocin (MLD-STZ) similarly upregulate the T helper (Th)1-type proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in islets of both the diabetes-susceptible male and the diabetes-resistant female C57BL/6 mice and that MLD-STZ downregulates the anti-inflammatory Th2-type cytokines interleukin (IL)-4 and IL-10, as well as the anti-inflammatory Th3-type cytokine-transforming growth factor (TGF)-ss1 in islets of male, but not female, mice. Thus, diabetes is associated with a relative preponderance of local proinflammatory cytokines. Here, we investigated the effects of MLD-STZ on the anti-inflammatory cytokine IL-11 and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-alpha) of NF-kappaB inhibitor (IkappaB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-alpha, NF-kappaB, and AP-1 was analyzed in islets. Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF-alpha and IFN-gamma response; and stimulated IL-4 production and inhibited activation of IKK-alpha, NF-kappaB, and AP-1. The results demonstrated the potential of rhIL-11 in preventing MLD-STZ diabetes through enhancement of anti-inflammatory responses in islets. In this process, the transcription factors NF-kappaB and AP-1 might play a key role.


miR-192-5p Silencing by Genetic Aberrations Is a Key Event in Hepatocellular Carcinomas with Cancer Stem Cell Features.
Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in an HCC cohort (n = 241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n = 613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC+ HCC. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC+ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis. SIGNIFICANCE: miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis.


Relative productivity of nurse practitioner and resident physician care models in the pediatric emergency department.
Duty hour restrictions limit the use of resident physicians in pediatric emergency departments (PEDs). We sought to determine the relative clinical productivity of PED attending physicians working with residents compared with PED attending physicians working with nurse practitioners (NPs). In a tertiary care PED with multiple care models (PED attending physicians with residents and/or fellows, PED attending physicians with NPs, PED attending physicians alone), we identified periods when care was provided concurrently and exclusively by a PED attending physician with 1 to 2 residents (resident pod) and a PED attending physician with 1 NP (NP pod). Billing records were reviewed to determine relative value units (RVUs) generated and patients seen by each PED attending physician. Emergency Severity Index (ESI) triage scores were used to compare patient acuities. The NP pods generated 5.35 RVUs per hour and the resident pods generated 4.35 RVUs per hour, with a significant difference of 1.00 RVUs per hour (95% confidence interval, 0.19-1.82). The NP pods saw 2.18 patients per hour, whereas the resident pods saw 1.90 patients per hour. This difference of 0.28 was not statistically significant (95% confidence interval, -0.07 to 0.62). Patient acuity was similar. Thirteen percent of the NP pod patients had the highest triage severity levels of ESI-1 and ESI-2, whereas 19% of the resident pod patients were ESI-1 and ESI-2 (P = 0.06). Pediatric emergency department attending physicians in an NP care model had greater clinical productivity, measured by RVUs, than PED attending physicians in a resident care model while treating similar patient populations.


Covid-19 and age discrimination: benefit maximization, fairness, and justified age-based rationing.
Age-based rationing remains highly controversial. This question has been paramount during the Covid-19 pandemic. Analyzing the practices, proposals, and guidelines applied or put forward during the current pandemic, three kinds of age-based rationing are identified: an age-based cut-off, age as a tiebreaker, and indirect age rationing, where age matters to the extent that it affects prognosis. Where age is allowed to play a role in terms of who gets treated, it is justified either because this is believed to maximize benefits from scarce resources or because it is believed to be in accordance with the value of fairness understood as (a) fair innings, where less priority is given to those who have lived a full life or (b) an egalitarian concern for the worse off. By critically assessing prominent frameworks and practices for pandemic rationing, this article considers the balance the three kinds of age-based rationing strike between maximizing benefits and fairness. It evaluates whether elements in the proposals are, in fact, contrary to the justifications of these measures. Such shortcomings are highlighted, and it is proposed to adjust prominent proposals to care for the worse off more appropriately and better consider whether the acquired benefits befalls the young or the old.


Guanidine and guanidinium cation in the excited state--theoretical investigation.
Diverse ab initio and density-functional-theory methods were used to investigate geometries, energies, and electronic absorption spectra of guanidine and its protonated form, as well as their photo-deactivation processes. It was shown that the guanidine is a weakly absorbing species with the excitation spectrum consisting mostly of transitions to the Rydberg excited states and one valence n-π4 state. The lowest energy band has a maximum at ca. 6.9 eV (∼180 nm). The protonation of guanidine affects its excitation spectrum substantially. A major shift of the Rydberg states to higher energies is clearly visible and strongly absorbing transitions from the ground state to the π3-π4 and π2-π4 states appears at 7.8 eV (∼160 nm). Three low-lying conical intersections (two for guanidine and one for protonated guanidine) between the ground state and the first excited singlet state were located. They are accessible from the Franck-Condon region through amino N-H stretching and out-of-plane deformations in guanidine and protonated guanidine, respectively. The relaxation of the π3-3s Rydberg state via amino N-H bond stretching was hindered by a barrier. The nondissociated conical intersection in protonated guanidine mediates the radiationless deactivation of the compound after excitation into the π3-π4 state. This fact is detrimental for the photostability of guanidine, since its conjugate acid is stable in aqueous solution over a wide pH range and in protein environment, where guanidinium moiety in arginine is expected to be in a protonated form.


[Modification of 3-methylcholanthrene-induced blastomogenesis in BALB/c mice by using the subcellular components of Bac. megaterium H].
It is shown that the cytoplasm of Bac. megaterium H possessing the antigenic affinity with the malignant tumour cells, being injected 7 days before the 3-methylcholanthrene injection promotes intensification of its blastomogenic effect, reduces both the period of tumour appearance and longevity of the tumour-bearing animals. On the contrary the cell wall preparation under the similar conditions, produces a therapeutic effect. An assumption is advanced that the effect of these preparations is associated with their different influence on the immune system.


Reverse phase protein arrays in signaling pathways: a data integration perspective.
The reverse phase protein array (RPPA) data platform provides expression data for a prespecified set of proteins, across a set of tissue or cell line samples. Being able to measure either total proteins or posttranslationally modified proteins, even ones present at lower abundances, RPPA represents an excellent way to capture the state of key signaling transduction pathways in normal or diseased cells. RPPA data can be combined with those of other molecular profiling platforms, in order to obtain a more complete molecular picture of the cell. This review offers perspective on the use of RPPA as a component of integrative molecular analysis, using recent case examples from The Cancer Genome Altas consortium, showing how RPPA may provide additional insight into cancer besides what other data platforms may provide. There also exists a clear need for effective visualization approaches to RPPA-based proteomic results; this was highlighted by the recent challenge, put forth by the HPN-DREAM consortium, to develop visualization methods for a highly complex RPPA dataset involving many cancer cell lines, stimuli, and inhibitors applied over time course. In this review, we put forth a number of general guidelines for effective visualization of complex molecular datasets, namely, showing the data, ordering data elements deliberately, enabling generalization, focusing on relevant specifics, and putting things into context. We give examples of how these principles can be utilized in visualizing the intrinsic subtypes of breast cancer and in meaningfully displaying the entire HPN-DREAM RPPA dataset within a single page.


Misalignment between Clinical Mold Antigen Extracts and Airborne Molds Found in Water-damaged Homes.
Rationale: Epidemiologic studies have demonstrated that exposure to molds and other fungi can play a role in a variety of allergic and pulmonary diseases in susceptible individuals. Species-specific mold antigen extracts are used in the clinical evaluation of suspected mold-related conditions; however, alignment between these extracts and the species of molds identified in the indoor environment of water-damaged homes has not been rigorously evaluated. Objectives: To identify the predominant genera and species of mold in the air of homes with water damage, mold growth, and/or occupants with respiratory complaints (complaint homes), and to assess their alignment with the mold antigen extracts used in clinical practice. Methods: The genera and species of molds identified in culture-type outdoor and indoor air samples collected from complaint homes throughout the United States and Canada from 2002 to 2017 were examined. Mold antigen extracts available and utilized for skin and serum testing in clinical practice were assessed, and alignment between these data were evaluated. Results: Culture data from 24,455 indoor air samples from 7,547 complaint homes and 29,493 outdoor samples were evaluated. Mean exposure values (colony-forming units [cfu]/m3) were calculated for each genus and species and indoor versus outdoor values were compared. Penicillium was the predominant genus identified in water-damaged homes, with a mean exposure (233.3 cfu/m3) 2.9 times higher than that of the Aspergillus genus (81.4 cfu/m3). Five Penicillium (P. aurantiogriseum, P. brevicompactum, P. citrinum, P. crustosum, and P. variabile) and three Aspergillus (A. versicolor, A. sydowii, and A. niger) species were identified as the predominant indoor water-damage-related fungi. However, none of these Penicillium species and only one of the Aspergillus species is currently available as an antigen extract for use in skin testing or serum testing panels. Conclusions: Significant misalignment exists between the currently available mold antigen extracts and the predominant species of molds found in water-damaged homes. Improving alignment has the potential to enhance diagnosis of mold-related diseases, including allergic asthma and hypersensitivity pneumonitis and to improve patient outcomes via interventions, including antigen avoidance through building remediation and occupant relocation, consistent with the findings of a recent American Thoracic Society Workshop Report.


Formatting an experiential learning education module to encourage dysphagia assessment in apheresis patients.
Dysphagia screening is oftentimes a focus of hospitalized patients, but dysphagia can also occur in outpatient settings. Dysphagia can be overlooked by nurses and clinicians, and it is therefore important to educate nurses on the importance of dysphagia screenings. This was a randomized prospective pilot study to compare the effect of experiential learning versus traditional PowerPoint learning regarding nurses' attitudes towards performing dysphagia screening in an outpatient setting. Twelve pre and post-test surveys were collected from nurses working in outpatient apheresis about their attitudes towards dysphagia screening. Additionally, 128 electronic medical records (EMR) were reviewed to determine if education increased the occurrence of dysphagia screening. There was a statistically significant difference in the pre vs. post-test group scores (P < .001), but due to small sample size, there was insufficient evidence to reject the null hypothesis that nurses had changed their attitudes towards dysphagia screening. Comparing documentation of dysphagia assessment in the EMR, there was not a significant difference in practice before or after the educational intervention (P = 0.18). The study results showed that the both types of teaching strategies are possible with nurses and they were receptive to both. Although the results of this study did not show a significant difference in practice, more research is needed to determine how to raise awareness and put this into practice.


Measurement of thrombopoietic levels: clinical and biological relationships.
Platelet production is primarily regulated by the thrombopoietic cytokine thrombopoietin (TPO). In most cases thrombopoietin serum levels are determined by the rate of c-mpl receptor-mediated degradation after TPO uptake into platelets and megakaryocytes. The contribution of increased TPO protein synthesis by a translational mechanism was recently appreciated as the cause for hereditary thrombocythemia and will have to be elucidated in other conditions of thrombocytosis in association with increased TPO levels.


[The future of psychotherapy in psychosomatic medicine].
To review the current perspectives and trends of psychotherapy as a key area of psychosomatic medicine with regard to both societal and scientific challenges as well as patient health care services. Also, to draw conclusions regarding the future training and practice of psychosomatic medicine and psychotherapy. Psychotherapy is confronted with many new challenges because of the high prevalence of mental and psychosomatic disorders, because of their increasing recognition as major health problems and because of the rapid technological and demographic changes going on in modern society. Despite its growth, psychotherapeutic care is still limited in many, especially rural, regions and for patients with complex psychosomatic and somatopsychic disorders. New models of training as well as integrated and multimodal care are needed in order to provide both, rapid, low-threshold and specialized, disorder-specific care.


Molecular characterization and applications of recombinant scFv antibodies to CD152 co-stimulatory molecule.
Recombinant human monoclonal antibodies against CD152 have been generated by selecting a synthetic phage scFv library with purified CD152-Ig fusion protein. Sixteen scFv fragments were isolated which specifically react with CD152 by enzyme-linked immunoabsorbent assay (ELISA) and Western blot resulting in their clustering into two groups recognizing different antigenic determinants. One group of scFvs (#3, #13, #40, #44, #47, #51, #57, #80 #83) recognized an epitope on CD152 dimer whereas another group (#15, #18, #31, #35, #54, #72, #81) recognized an epitope on both dimeric and monomeric CD152 molecule suggesting their possible use in understanding the subunit structure of CD152 which is still controversial. Sequencing of the VH genes revealed that all the scFvs belonged to the VH3 gene family but they were different in CDR3 length and composition. It was possible to correlate specific CDR3 sequences with reactivity of the two groups of scFvs. Four scFvs, #3, #40, #81 and #83, each representative of one specific CDR3, were selected for further analysis. Competition ELISA experiments showed that they recognize CD152 in its native configuration and bound to different epitopes from the CD80/CD86 interaction site. The scFvs were able to stain human T lymphocytes stimulated either with anti-CD3 and CD28 antibodies or PHA, PMA and ionomycin by cytofluorimetry suggesting that they can be useful reagents for monitoring the kinetics of surface-bound and intracellular CD152.


Jonathan Rosen: building a dynamic union-based health and safety program.
Jonathan Rosen has spent more than 30 years building union-based health and safety programs. In the 1970s he was a union activist. In 1980 he became a union health and safety committee chair at a Milwaukee manufacturing firm. Following that, he had a nearly 20-year career with the New York State Public Employees Federation (PEF). He trained as an industrial hygienist and developed a highly regarded public sector union-based health and safety program. PEF's Health and Safety Department supported a network of union health and safety committees. Program accomplishments included innovative work on workplace violence prevention, indoor environmental quality, infectious diseases, and ergonomics. Mr. Rosen promoted collaboration among unions, helped support new activists, advocated tirelessly for injured workers, and formed an effective alliance with researchers. Rosen discusses essential strategies for mobilizing union members and gaining commitment to health and safety from unions, employers, and policy makers.


Interviewing children in custody cases: implications of research and policy for practice.
Research on child interviewing has burgeoned over the past 25 years as expectations about children's agency, competence, and participation in society have changed. This article identifies recent trends in research, policy, and theory with implications for the practice of interviewing children in cases of contested divorce and for the weight to be given the information children provide. A number of fields of relevant research are identified, including studies of families who have participated in the family law system, studies of child witnesses in the field, experimental studies of the effects of interview techniques on children's memory and suggestibility, and ethnographic methods that elicit children's views of their own experiences. Finally, a set of 10 principles for practice are delineated based on the best available science.


[Chronic thromboembolic pulmonary hypertension].
Acute pulmonary hypertension has a high mortality at the onset. Patients surviving the first phase will usually recanalize the pulmonary arteries through intrinsic thrombolytic mechanisms and medical treatment. However, in some cases there is insufficient resolution of the emboli with subsequent thrombotic and fibrotic reorganization, leading to a worsening of the pulmonary obstruction. In the open pulmonary arteries the disease may lead to hypertrophy of the media and intimal proliferation, thus leading to a further increase in the pulmonary vascular resistance. This again leads to hypertrophy of the right ventricle and ultimately to right-sided heart failure. Untreated, chronic thromboembolic pulmonary hypertension has a five-year mortality approaching 100%, but extensive pulmonary thrombendarterectomy using extracorporeal circulation and deep hypothermia has been shown to lower the pulmonary vascular resistance and thereby improve the prognosis significantly. Operative treatment can now be offered in Denmark, and the purpose of this review is to draw attention to the disease, its symptoms, diagnosis and the surgical treatment.


Diagnostic accuracy of retrospective application of the Vesical Imaging-Reporting and Data System: preliminary results.
To evaluate the retrospective accuracy of the Vesical Imaging-Reporting and Data System (VI-RADS) in detecting muscle invasion in bladder cancer. We investigated patients who underwent pelvic magnetic resonance imaging and were submitted to transurethral resection of a bladder tumor between 2015 and 2018. Thirty cases were reviewed by radiologists blinded to the final clinical stage. The VI-RADS score was applied and compared with the histopathological findings in the surgical specimen. Of the 30 patients with suspicious bladder lesions, 5 (16.6%) had benign histopathological findings, 17 (56.6%) had non-muscle-invasive bladder cancer, and 8 (26.6%) had muscle-invasive bladder cancer. The optimal criterion to detect muscle-invasive bladder cancer was a final VI-RADS score > 3, for which the sensitivity and specificity were 100% (95% CI: 56.0-100%) and 90.9% (95% CI: 69.3-98.4%), respectively. The VI-RADS appears to estimate correctly the degree of muscle invasion in suspicious bladder lesions. However, prospective studies evaluating larger samples are needed in order to validate the method.


Photo-controlled release of zinc metal ions by spiropyran receptors anchored to single-walled carbon nanotubes.
Light controllable release of antinflammatory zinc ions by a smart multifunctional material composed of spiropyrans and single walled carbon nanotubes (SWNTs) is demonstrated. The exploitation of a number of complementary characterization techniques allows the investigation of both composition and performance of the multifunctional SP/SWNT nanomaterial developed. Moreover, its suitability for potential applications in bio-systems is suggested by the effective removal of the metal catalyst and the introduction of biocompatible linkers into the SP/SWNT material. The realization of potential photo controllable SP/SWNTs based drug delivery systems (DDSs) is envisaged, where nanotubes act as intracellular carriers of light modulated receptors for bioactive agents.


Analytic Global Regularized Backscatter Quantitative Ultrasound.
Although a variety of techniques have been developed to reduce the appearance of B-mode speckle, quantitative ultrasound (QUS) aims at extracting the hidden properties of the tissue. Herein, we propose two novel techniques to accurately and precisely estimate two important QUS parameters, namely, the average attenuation coefficient and the backscatter coefficient. Both the techniques optimize a cost function that incorporates data and continuity constraint terms, which we call AnaLytical Global rEgularized BackscatteR quAntitative ultrasound (ALGEBRA). We propose two versions of ALGEBRA, namely, 1-D- and 2-D-ALGEBRA. In 1-D-ALGEBRA, the regularized cost function is formulated in the axial direction, and the QUS parameters are calculated for one line of radio frequency (RF) echo data. In 2-D-ALGEBRA, the regularized cost function is formulated for the entire image, and the QUS parameters throughout the image are estimated simultaneously. This simultaneous optimization allows 2-D-ALGEBRA to "see" all the data before estimating the QUS parameters. In both the methods, we efficiently optimize the cost functions by casting it as a sparse linear system of equations. As a result of this efficient optimization, 1-D-ALGEBRA and 2-D-ALGEBRA are, respectively, 600 and 300 times faster than optimization using the dynamic programming (DP) method previously proposed by our group. In addition, the proposed technique has fewer input parameters that require manual tuning. Our results demonstrate that the proposed ALGEBRA methods substantially outperform least-square and DP methods in estimating the QUS parameters in phantom experiments.


Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway.
Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.


Stages and demands in the careers of Canadian National Hockey League players.
Researchers have identified some demands of Canadian National Hockey League (NHL) players, yet there is little direction for players hoping to reach the lucrative league. The objectives of this study were to identify the stages, statuses and demands in Canadian NHL players' careers and propose an empirical career model of Canadian NHL players. In total, 5 rookies, 5 veterans and 13 retirees had their interviews undergo an interpretive thematic analysis. Prospects face the NHL combine, training camp and minor league assignment. While developing into NHL players, rookies deal with NHL call-ups, team competition and formative production while sophomores seemed preoccupied by the opposition. Prime veterans become All-Stars by garnering point production and challenging for the Stanley Cup while seasoned veterans remain relevant through training camps. A discussion about the model's viability is followed by applications for sport psychology researchers and practitioners.


High-dose therapy with hematopoietic cell transplantation for patients with central nervous system involvement by non-Hodgkin's lymphoma.
Central nervous system (CNS) involvement by non-Hodgkin's lymphoma (NHL) carries a poor patient prognosis whether it occurs as a primary site of disease or secondarily in patients with systemic disease. In a group of 481 patients undergoing high-dose therapy with hematopoietic cell transplantation (HCT) for NHL, 15 patients (3.1%) were identified with CNS involvement. Two patients had primary CNS lymphoma, and 13 had secondary disease. All patients received intrathecal chemotherapy, and 13 received CNS radiotherapy before transplantation. Fourteen patients received systemic chemotherapy. At the time of transplantation, both patients with primary CNS lymphoma and 8 patients with secondary disease had achieved a complete response, 3 patients had achieved a partial response, 1 had failed induction therapy, and 1 had progression of CNS disease before high-dose therapy. Fourteen patients received carmustine, etoposide, and cyclophosphamide as the preparative regimen, and 1 patient received fractionated total body irradiation instead of carmustine. The 2 patients with primary CNS lymphoma were alive and free of disease, 1 at 1,085 days after HCT and 1 at 3,704 days after HCT. The actuarial 5-year event-free survival (EFS) was 46% +/- 26%, and overall survival (OS) was 41% +/- 28%. The median EFS and OS were 2.2 and 1.5 years, respectively. Three patients experienced symptomatic memory loss or intellectual decline after therapy, 1 patient developed paraplegia, and 1 patient had a thrombotic stroke 20 months after HCT. Despite treatment-related toxicities, 7 patients responding to quality-of-life questions at approximately 1 year after HCT gave their overall quality of life a median rating of 9 out of a possible 10 (range, 6-10). High-dose therapy with autologous HCT can produce extended EFS in patients with secondary CNS lymphoma and possibly in those with primary CNS NHL.


Achirality in the low temperature structure and lattice modes of tris(acetylacetonate)iron(iii).
Tris(acetylacteonate) iron(iii) is a relatively ubiquitous mononuclear inorganic coordination complex. The bidentate nature of the three acetylacteonate ligands coordinating around a single centre inevitably leads to structural isomeric forms, however whether or not this relates to chirality in the solid state has been questioned in the literature. Variable temperature neutron diffraction data down to T = 3 K, highlights the dynamic nature of the ligand environment, including the motions of the hydrogen atoms. The Fourier transform of the molecular dynamics simulation based on the experimentally determined structure was shown to closely reproduce the low temperature vibrational density of states obtained using inelastic neutron scattering.


A computational study of whole-brain connectivity in resting state and task fMRI.
We compared the functional brain connectivity produced during resting-state in which subjects were not actively engaged in a task with that produced while they actively performed a visual motion task (task-state). In this paper we employed graph-theoretical measures and network statistics in novel ways to compare, in the same group of human subjects, functional brain connectivity during resting-state fMRI with brain connectivity during performance of a high level visual task. We performed a whole-brain connectivity analysis to compare network statistics in resting and task states among anatomically defined Brodmann areas to investigate how brain networks spanning the cortex changed when subjects were engaged in task performance. In the resting state, we found strong connectivity among the posterior cingulate cortex (PCC), precuneus, medial prefrontal cortex (MPFC), lateral parietal cortex, and hippocampal formation, consistent with previous reports of the default mode network (DMN). The connections among these areas were strengthened while subjects actively performed an event-related visual motion task, indicating a continued and strong engagement of the DMN during task processing. Regional measures such as degree (number of connections) and betweenness centrality (number of shortest paths), showed that task performance induces stronger inter-regional connections, leading to a denser processing network, but that this does not imply a more efficient system as shown by the integration measures such as path length and global efficiency, and from global measures such as small-worldness. In spite of the maintenance of connectivity and the "hub-like" behavior of areas, our results suggest that the network paths may be rerouted when performing the task condition.


Participant-Centered Strategies for Overcoming Barriers to Biospecimen Collection among Spanish-Speaking Latina Breast Cancer Survivors.
Latinos are underrepresented in biomedical research, particularly biomarker research, yet they constitute the nation's largest ethnic/racial minority. Optimal methods for obtaining biospecimens for biomarker research among Latinos need to be identified. To minimize barriers and enhance participation, this study developed and tested tailored strategies for collecting biomarkers of chronic stress and premature aging among Spanish-speaking Latina breast cancer survivors. This study used a community-based participatory approach and selected hair and saliva as noninvasive biospecimens to assess telomere length, the cortisol awakening response (CAR), and hair cortisol concentration. We developed bilingual multimedia instructional materials, and community health workers assisted in collections. Telephone surveys assessed willingness to participate in future studies, barriers to sample collection, and recommendations for improving the strategies. A total of 103 participants were recruited over 18 months from two rural sites in California, and 88 were retained at 6-month follow-up. At baseline, rates of donating salivary DNA for telomere length measurement, saliva for CAR analysis, and hair for cortisol concentration were 98%, 89%, and 52%, respectively. At follow-up, rates were 83%, 76%, and 55%, respectively. The majority of participants reported being very willing to provide hair (72%) or saliva (74%) for future studies. Our results support the feasibility of including minorities in biomedical research. We report excellent rates of saliva collection when community partners are engaged in the process, and when patient-centered and culturally tailored recruitment methods are implemented. The development of methods to facilitate the inclusion of minorities in biomedical research is critical to eliminate racial/ethnic health disparities.