New approach to evaluate retinal protection by intraocular lenses against age-related lipofuscin accumulation-mediated retinal phototoxicity.
To present a new approach for evaluating intraocular lenses (IOLs) for retinal protection from age-related lipofuscin accumulation-mediated phototoxicity. Alcon Laboratories Inc., Fort Worth, Texas, USA, and Cardiff University, Cardiff, United Kingdom. Age-related lipofuscin accumulation-mediated action spectra for retinal phototoxicity in an aphakic eye were created for this evaluation. Transmission curves for 6 IOLs and for cornea and spectral radiant power distribution for sunlight and 2 lamps were used. Pseudophakic action spectra and retinal phototoxicity for 3 wavelength ranges and 3 ages were computed. The percentage protection of each IOL was computed as the reduction in phototoxicity relative to the aphakic eye. Retinal phototoxicity increased 3.66 times from the third to ninth decade of age. The comparative retinal phototoxicity and retinal protection provided by IOLs were dependent on the light source and range of wavelength; however, unlike phototoxicity, retinal protection was independent of age. The 420 to 480 nm range was the most useful for discriminating protection by IOLs. Retinal phototoxicity significantly increased with age; however, the retinal protection by IOLs was independent of age. The interaction between the transmission curve of IOLs and light sources required inclusion of widely used lamps besides sunlight for evaluation of IOLs. For the 420 to 480 nm wavelength range, the 3 light sources clearly discriminated the protection provided by IOLs. The AcrySof Natural IOL (Alcon) provided the highest protection consistently for the tested light sources.


ClickGene: an open cloud-based platform for big pan-cancer data genome-wide association study, visualization and exploration.
Tremendous amount of whole-genome sequencing data have been provided by large consortium projects such as TCGA (The Cancer Genome Atlas), COSMIC and so on, which creates incredible opportunities for functional gene research and cancer associated mechanism uncovering. While the existing web servers are valuable and widely used, many whole genome analysis functions urgently needed by experimental biologists are still not adequately addressed. A cloud-based platform, named CG (ClickGene), therefore, was developed for DIY analyzing of user's private in-house data or public genome data without any requirement of software installation or system configuration. CG platform provides key interactive and customized functions including Bee-swarm plot, linear regression analyses, Mountain plot, Directional Manhattan plot, Deflection plot and Volcano plot. Using these tools, global profiling or individual gene distributions for expression and copy number variation (CNV) analyses can be generated by only mouse button clicking. The easy accessibility of such comprehensive pan-cancer genome analysis greatly facilitates data mining in wide research areas, such as therapeutic discovery process. Therefore, it fills in the gaps between big cancer genomics data and the delivery of integrated knowledge to end-users, thus helping unleash the value of the current data resources. More importantly, unlike other R-based web platforms, Dubbo, a cloud distributed service governance framework for 'big data' stream global transferring, was used to develop CG platform. After being developed, CG is run on an independent cloud-server, which ensures its steady global accessibility. More than 2 years running history of CG proved that advanced plots for hundreds of whole-genome data can be created through it within seconds by end-users anytime and anywhere. CG is available at http://www.clickgenome.org/.


Altitudinal movements of Guizhou snub-nosed monkeys (Rhinopithecus brelichi) in Fanjingshan National Nature Reserve, China: implications for conservation management of a flagship species.
Primate movements can include a substantial altitudinal component, depending on the complexity of the landscape and the distribution of the inherent vegetation zones. We investigated altitudinal movements of Guizhou snub-nosed monkeys (Rhinopithecus brelichi) at Fanjingshan National Nature Reserve, China. The monkeys ranged at elevations between 1,350 and 1,870 m with an overall mean of 1,660 m. We did not find a significant difference in the mean elevations among seasons or evidence of winter migration to lower elevations. The monkeys exhibited a distinct daily altitudinal movement pattern that coincided with their activities. During the day, the monkeys consistently traveled from lower to higher elevations in the morning (98% of records) and then descended to lower elevations in the afternoon (96%). Hence, the mean elevation of night roosts was significantly lower (1,561 m) than those of feeding sites and day roosts (1,735 and 1,737 m, respectively). We suggest that this daily pattern of R. brelichi may reflect a trade-off between finding food and avoiding predation within the mixed evergreen and deciduous broadleaf vegetation zone at the study site, which may constitute the most important habitat for R. brelichi in the reserve.


Individual and Neighborhood Stressors, Air Pollution and Cardiovascular Disease.
Psychosocial and environmental stress exposures across the life course have been shown to be relevant in the development of cardiovascular disease (CVD). Assessing more than one stressor from different domains (e.g., individual and neighborhood) and across the life course moves us towards a more integrated picture of how stress affects health and well-being. Furthermore, these individual and neighborhood psychosocial stressors act on biologic pathways, including immune function and inflammatory response, which are also impacted by ubiquitous environmental exposures such as air pollution. The objective of this study is to evaluate the interaction between psychosocial stressors, at both the individual and neighborhood level, and air pollution on CVD. This study used data from the 2009-2011 Behavioral Risk Factor Surveillance System (BRFSS) from Washington State. Adverse childhood experiences (ACEs) measured at the individual level, and neighborhood deprivation index (NDI) measured at the zip code level, were the psychosocial stressors of interest. Exposures to three air pollutants-particulate matter (both PM2.5 and PM10) and nitrogen dioxide (NO₂)-were also calculated at the zip code level. Outcome measures included several self-reported CVD-related health conditions. Both multiplicative and additive interaction quantified using the relative excess risk due to interaction (RERI), were evaluated. This study included 32,151 participants in 502 unique zip codes. Multiplicative and positive additive interactions were observed between ACEs and PM10 for diabetes, in models adjusted for NDI. The prevalence of diabetes was 1.58 (95% CI: 1.40, 1.79) times higher among those with both high ACEs and high PM10 compared to those with low ACEs and low PM10 (p-value = 0.04 for interaction on the multiplicative scale). Interaction was also observed between neighborhood-level stressors (NDI) and air pollution (NO₂) for the stroke and diabetes outcomes on both multiplicative and additive scales. Modest interaction was observed between NDI and air pollution, supporting prior literature on the importance of neighborhood-level stressors in cardiovascular health and reinforcing the importance of NDI on air pollution health effects. ACEs may exert health effects through selection into disadvantaged neighborhoods and more work is needed to understand the accumulation of risk in multiple domains across the life course.


[The effect of vilozen on the immune status of bronchial asthma patients].
An immunological study of 163 patients with different forms of bronchial asthma revealed a distinct disturbance of the cellular link of immunity in these patients. Vilosen (a native non-protein immunomodulator extracted from the thymus of animals) possessing a prevailing action on T-cells was used for correction of the immune disorders. It was found that vilosen proved effective in the complex treatment of patients with atopic associated forms of bronchial asthma.


Opioid tolerance impacts compliance with enhanced recovery pathway after major abdominal surgery.
Opioid tolerant patients have been shown to have poor postoperative outcomes. Enhanced recovery pathways are evidence-based interventions that focus on optimizing recovery, and their effectiveness depends on the degree of compliance with the pathway. We wish to determine pathway compliance and its impact on postoperative outcomes in opioid tolerant patients undergoing abdominal surgery on an enhanced recovery pathway. From December 2014 to June 2017, 646 patients undergoing major abdominal surgery on an enhanced recovery pathway were included. Patients <18 years and having emergency surgery were excluded. Compliance was measured to 14 perioperative pathway standards and high-compliance was defined as adhering to ≥75% standards. Opioid tolerance was defined as any patient taking a prescribed opioid medication equivalent to 60 mg of oral morphine per day for 1 week prior to surgery. The Colorectal Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity was used for risk-adjusted analyses. Outcomes of interest include length of stay, major complications (Clavien-Dindo ≥2), 30-day readmission rates, and mortality. Overall, 114 (18%) patients were opioid tolerant and 532 (82%) were not opioid tolerant. Opioid tolerant patients were less likely to be highly compliant with enhanced recovery pathway standards than non-tolerant patients (35% vs 54%; P < .001); particularly postoperative care standards. On adjusted analysis, opioid tolerance was associated with a 2-fold increase in readmissions following major abdominal surgery. Examining only those patients with opioid tolerance, adjusted analysis demonstrated that high compliance with the enhanced recovery pathway standards was independently associated with a 26% reduction in length of stay, over a 90% reduction in major complications, and mitigated the effect on readmissions. The authors provide evidence that opioid tolerance is associated with less favorable outcomes in patients undergoing major abdominal surgery on an enhanced recovery pathway, and this is likely due to a lack of pathway compliance. Establishing strategies to improve compliance in this challenging patient cohort may serve to mitigate the negative impact of opioid tolerance.


INTRAVENOUS IOPAMIDOL PHARMACOKINETICS IN COMMON CARP (CYPRINUS CARPIO).
Koi carp (Cyprinus carpio), a variety of common carp, has gained popularity as an ornamental fish worldwide. Their high monetary and sentimental value has necessitated the development of antemortem diagnostic options. Contrast-enhanced computed tomography (CT) scanning with intravenous iopamidol has been shown to be safe and diagnostically effective at a minimum dose of 480 mg iodine (I)/kg in koi. The purpose of this study was to evaluate the pharmacokinetic parameters of this dose of iopamidol, as well as excretory mechanisms specific to fish, using common carp as a model. Blood, posterior kidney, gill, and bile were collected, necessitating sacrificial sampling. Thirty-five adult fish were randomly divided into six sampling groups. Five sampling groups (n = 6/group) received 480 mg I/kg; the control group (n = 5) received an equivalent volume of saline. The iopamidol groups were sampled at the following time points postinjection: 5 min, 1 hr, 6 hr, 24 hr, and 48 hr. The control group was sampled at 48 hr. Concentrations of iopamidol were determined using liquid chromatography tandem mass spectrometry; noncompartmental analysis was used to calculate pharmacokinetic parameters. Total clearance (3.04 ml/hr per kilogram) was slower, the volume of distribution smaller (79.92 ml/ kg), and the elimination half-life (20.39 hr) prolonged compared to similar studies in mammals. The time-concentration profiles of kidney and gill were similar; these organs appear to be responsible for the majority of iopamidol excretion. However, that of bile was much different, showing slower, low-level accumulation with time, suggesting that in fish, multiple organ systems play a role in elimination beyond just the kidney. In particular, they may rely more heavily upon biliary excretion, which thus far has been noted only in mammals with renal impairment. Further research is warranted to investigate if the slower elimination allows diagnostic CT images to be acquired at different time points postinjection.


Adhesion of coagulase-negative staphylococci to methacrylate polymers and copolymers.
Adhesion of coagulase-negative staphylococci (CNS) was studied onto a homologous series of methacrylate polymers and copolymers. The materials varied in wettability (contact angles) and were either positively or negatively charged (zeta-potential). Bacterial adhesion experiments performed in a parallel-plate perfusion system showed that positively charged TMAEMA-Cl copolymers significantly promoted the adhesion of CNS as compared with all other methacrylate (co)polymers tested. The bacterial adhesion rates onto the positively charged surfaces are diffusion-controlled, whereas those onto the surfaces with a negative zeta-potential are more surface-reaction-controlled due to the presence of a potential energy barrier. The bacterial adhesion rates onto various poly (alkyl methacrylates) were similar. The number of adhering bacteria onto the negatively charged MMA/MAA copolymer did not differ from that onto pMMA, indicating that sufficient sites on the copolymer surface with the same potential energy barrier as that on pMMA, were available for adhesion. Decreasing rates of adhesion of CNS were observed onto MMA/HEMA copolymers with increasing HEMA content coinciding with increasing hydrophilicity. Low plateau values for the bacterial adhesion were observed on 50MMA/50HEMA, pHEMA, and 85HEMA/15MAA, indicating that the adhesion onto these materials was reversible. Four CNS strains with different surface characteristics all showed higher numbers of adhering bacteria onto 85MMA/15TMAEMA-Cl than onto 85MMA/15MAA and pMMA.


Measuring population health outcomes.
An ideal population health outcome metric should reflect a population's dynamic state of physical, mental, and social well-being. Positive health outcomes include being alive; functioning well mentally, physically, and socially; and having a sense of well-being. Negative outcomes include death, loss of function, and lack of well-being. In contrast to these health outcomes, diseases and injuries are intermediate factors that influence the likelihood of achieving a state of health. On the basis of a review of outcomes metrics currently in use and the availability of data for at least some US counties, I recommend the following metrics for population health outcomes: 1) life expectancy from birth, or age-adjusted mortality rate; 2) condition-specific changes in life expectancy, or condition-specific or age-specific mortality rates; and 3) self-reported level of health, functional status, and experiential status. When reported, outcome metrics should present both the overall level of health of a population and the distribution of health among different geographic, economic, and demographic groups in the population.


Criteria for surveys: from the European Association of Cardiovascular Imaging Scientific Initiatives Committee.
The European Association of Cardiovascular Imaging (EACVI) is committed to maintaining the highest standards of professional excellence in all aspects of cardiovascular imaging. The mission of the EACVI is to promote excellence in clinical diagnosis, research, technical development, and education in cardiovascular imaging with a particular focus on education, training, scientific initiatives, and research. The EACVI established the Scientific Initiatives Committee (SIC) in December 2018. This committee has responsibility for surveys among imagers, patients' surveys and surveys including data from clinical practice. The current document describes the aims of the EACVI SIC and the creation of the international EACVI survey network. This document summarizes the EACVI's standards for the survey questions and standards for writing the papers with the results of the surveys. These are in accordance with previous recommendations and were approved by the EACVI SIC and the EACVI Board in 2019.


Docetaxel, cisplatin and 5-fluorouracil adjuvant chemotherapy following three-field lymph node dissection for stage II/III N1, 2 esophageal cancer.
To determine the efficacy of postoperative adjuvant chemotherapy with docetaxel + cisplatin + 5-fluorouracil (DCF) in lymph node metastasis-positive esophageal cancer, we retrospectively analyzed 139 patients with stage II/III (non-T4) esophageal cancer with lymph node metastasis (1-6 nodes), who did not receive preoperative treatment and underwent three-field lymph node dissection in the Juntendo University Hospital between December, 2004 and December, 2009. The tumors were histologically diagnossed as squamous cell carcinoma. The patients were divided into two groups, a surgery alone group (S group, 88 patients) and a group that received postoperative DCF therapy (DCF group, 51 patients). The disease-free and overall survival were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as N1 and N2, according to the TNM classification. There were no significant differences between the S and DCF groups regarding clinicopathological factors other than intramural metastasis and main tumor location. The presence of intramural metastasis, blood vessel invasion and the number of lymph nodes were identified as prognostic factors. The 5-year disease-free and overall survival were 55.8 and 57.3%, respectively, in the S group and 52.8 and 63.0%, respectively, in the DCF group. These differences were not considered to be statistically significant (P=0.789 and 0.479 for disease-free and overall survival, respectively). Although there were no significant differences in disease-free and overall survival between the S and DCF groups in N1 cases, both disease-free and overall survival were found to be better in the DCF group (54.2 and 61.4%, respectively) compared to the S group (29.6 and 28.8%, respectively) in N2 cases (P=0.029 and 0.020 for disease-free and overall survival, respectively). Therefore, postoperative adjuvant chemotherapy with DCF was shown to improve disease-free and overall survival in moderate lymph node metastasis-positive cases (N2), suggesting that the DCF regimen may be effective as postoperative adjuvant chemotherapy for patients with lymph node metastasis from esophageal cancer.


Screen-based analysis of magnetic nanoparticle libraries formed using peptidic iron oxide ligands.
The identification of effective polypeptide ligands for magnetic iron oxide nanoparticles (IONPs) could considerably accelerate the high-throughput analysis of IONP-based reagents for imaging and cell labeling. We developed a procedure for screening IONP ligands and applied it to compare candidate peptides that incorporated carboxylic acid side chains, catechols, and sequences derived from phage display selection. We found that only l-3,4-dihydroxyphenylalanine (DOPA)-containing peptides were sufficient to maintain particles in solution. We used a DOPA-containing sequence motif as the starting point for generation of a further library of over 30 peptides, each of which was complexed with IONPs and evaluated for colloidal stability and magnetic resonance imaging (MRI) contrast properties. Optimal properties were conferred by sequences within a narrow range of biophysical parameters, suggesting that these sequences could serve as generalizable anchors for formation of polypeptide-IONP complexes. Differences in the amino acid sequence affected T1- and T2-weighted MRI contrast without substantially altering particle size, indicating that the microstructure of peptide-based IONP coatings exerts a substantial influence and could be manipulated to tune properties of targeted or responsive contrast agents. A representative peptide-IONP complex displayed stability in biological buffer and induced persistent MRI contrast in mice, indicating suitability of these species for in vivo molecular imaging applications.


Perspectives on evidence based practice in ABI rehabilitation. "Relevant Research": who decides?
Growing evidence suggests that acquired brain injury (ABI) rehabilitation and research should be guided by a philosophy that focuses on: restoration, compensation, function and participation in all aspects of daily life. Such a broad, more pluralistic approach influences ABI rehabilitation research at a number of levels, including both the generation of evidence, and in searching for, critiquing and applying the evidence to practice. The objective of evidence based medicine/practice (EBM/EBP) is to apply and integrate clinical expertise with evidence gained through systematic research and scientific inquiry to medical/clinical practice. While there is abundant literature debating the practical and sociological implications of EBP, there has been limited examination of EBP within the inherently complex nature of ABI rehabilitation and rehabilitation research. This paper provides a framework for clinical decision making regarding evidence based practice in the context of ABI rehab including: 1. A discussion of the purpose of evidence based practice, 2. Levels of evidence relevant to ABI rehabilitation research, and 3. A rationale for incorporating a broader, more pluralistic concept of evidence or "person-centred EBP". We conclude with a series of key questions for the evaluation and application of systematic reviews of the evidence in the context of ABI rehabilitation.


Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM).
Three intensive consolidation strategies are currently proposed to younger adults with acute myeloid leukemia (AML) in first complete remission (CR): allogeneic or autologous bone marrow transplantation (BMT) and intensive consolidation chemotherapy (ICC). Patients aged 15 to 50 years with de novo AML received an induction treatment with 7 days of cytarabine and either idarubicin or rubidazone. After achievement of a CR, patients up to the age of 40 and having an HLA-identical sibling were assigned to undergo an allogeneic BMT. All the other patients received a first course of ICC with high-dose cytarabine and the same anthracycline as for induction. They were then randomly assigned to either receive a second course of ICC with amsacrine and etoposide or a combination of busulfan and cyclosphosphamide followed by an unpurged autologous BMT. Of 517 eligible patients, 367 had a CR, but only 219 (59.5%) actually received the planned intensive postremission treatment (73 allogeneic BMT, 75 autologous BMT, and 71 ICC). With a median follow-up of 62 months, the 4-year disease-free survival (DFS) of the 367 patients in CR was 39.5%. The 4-year overall survival (OS) of the 517 eligible patients was 40.5%. In multivariate analysis, DFS and OS were influenced only by the initial white blood cell count and by the French-American-British classification. The type of postremission therapy had no significant impact on the outcome. There was no difference in the 4-year DFS and OS between 88 patients for whom an allogeneic BMT was scheduled (respectively, 44% and 53%) and 134 patients of the same age category and without an HLA-identical sibling (respectively, 38% and 53%). Similarly, there was no difference in the outcome between autologous BMT and ICC. The 4-year DFS was 44% for the 86 patients randomly assigned to autologous BMT and 40% for the 78 patients assigned to ICC (P = .41). The 4-year OS was similar in the two groups (50% v 54.5%, P = .72). The median duration of hospitalization and thrombocytopenia were longer after autologous BMT (39 v 32 days, P = .006, and 109.5 v 18.5 days, P = .0001, respectively). After a first course of ICC, a second course of chemotherapy is less myelotoxic than an unpurged autologous BMT but yields comparable DFS and OS rates.


Influence of substituent and benzoannulation on photophysical properties of 1-benzoylmethyleneisoquinoline difluoroborates.
A series of 1-benzoylmethyleneisoquinoline difluoroborates were synthesized, and their photophysical properties were determined. The effect of the substituent and benzoannulation on their properties was investigated to make a comparison with recently published results focused on related quinolines. The photophysical properties of isoquinoline derivatives differ from those of quinolines, and the most pronounced differences are found for the fluorescence quantum yields. Both experimental and theoretical approaches were used to explain the observed photophysical properties.


A single gene difference determines relative susceptibility to caffeine-induced lethality in SWR and CBA inbred mice.
Inbred mouse strains SWR and CBA differ markedly in their relatively susceptibility to the acute toxic effects of intraperitoneally administered caffeine. At a dose of 187 mg/kg, SWR mice survive a stress-potentiated lethality test apparently related to the generation of tonic seizures; in contrast, CBA mice usually die in less than 30 seconds after this dose. Progeny from several different genetic crosses were characterized to determine the genetic basis underlying this phenotypic difference in caffeine sensitivity. F1 progeny from reciprocal crosses of the parental strains were uniformly sensitive to caffeine-induced lethality, i.e., caffeine responsiveness behaves like an autosomal dominant trait. Self-crossing of F1 individuals produced both progeny which were resistant to caffeine-induced lethality (26% of the total) and those which were susceptible (74%). Backcrosses of the F1 animals to the CBA parent produced no (0/19) resistant progeny. In contrast, backcrosses of F1 animals to SWR produced 54% resistant progeny. These data indicate that the difference in susceptibility to caffeine-induced lethality between these strains is determined by a single pair of autosomal alleles in which susceptibility (responsiveness) to this methylxanthine is dominant to resistance (nonresponsiveness).


Can Pre-Pregnancy Body Mass Index and Maternal Exercise Affect Birth and Neonatal Outcomes-A Cross Sectional Study.
There has been a dramatic worldwide increase in the prevalence of obesity or overweight and physical inactivity in women of reproductive age. Growing evidence suggests that pre-pregnancy maternal abnormal body mass index (BMI) and lower physical activity level are associated with poor maternal health and perinatal outcomes. The aim of this study was to assess how self-perceived exercise and pre-pregnancy BMI are associated with preterm birth, low birth weight, and type of birth. We conducted a retrospective cross-sectional study of 394 Polish women in the postpartum period. We used a questionnaire with the structure of the medical interview. To analyze factors related to birth outcomes, we used the Pearson's Chi-squared test of independence and odds ratio (OR), with a corresponding 95% confidence interval (CI), followed by a multiple logistic regression. Women who reported being physically active before pregnancy (p = 0.00) and during pregnancy (p = 0.03) were more likely to give birth on time and had a lower incidence of very-premature and extremely premature births compared to inactive women. Importantly, they were more likely to have vaginal birth (p = 0.03). Pre-pregnancy BMI influenced the week of delivery, i.e., inadequate, too-high BMI contributed to an increase in the percentage of premature births [OR (95% CI) = 1.19 (1.06; 1.34)]. The findings indicate that promoting physical activity and weight management remains a priority in public health policy, and women of childbearing age should be encouraged to adopt or maintain an active and healthy lifestyle during pregnancy in order to avoid sedentary- and obesity-associated risks affecting birth and newborns' health.


Sacubitril-valsartan versus enalapril for acute decompensated heart failure: a cost-effectiveness analysis.
The Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilised from an Acute Heart Failure Episode (PIONEER-HF) trial demonstrated significant reductions in N-terminal pro-B-type natriuretic peptide. Our study explored the cost-effectiveness of the use of sacubitril-valsartan versus enalapril in acute decompensated heart failure from the Australian healthcare perspective. A Markov model was designed using data from the PIONEER-HF trial to model the clinical progress and costs of patients over a lifetime time horizon. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for acute decompensated heart failure' or 'dead'. Costs and utilities were estimated from published sources. The cost of sacubitril-valsartan (per the Australian pharmaceutical benefits schedule) was AU$7.08/day. Outcomes of interest were the incremental cost-effectiveness ratios in terms of cost per quality-adjusted life year gained and cost per year of life saved. Cost and benefits were discounted at 5.0% per annum. Compared to enalapril, sacubitril-valsartan was estimated to cost an additional AU$7464 (discounted) per person, but lead to 0.127 years of life saved (discounted) and 0.096 quality-adjusted life years gained (discounted) over a lifetime analysis. These equated to incremental cost-effectiveness ratios of AU$58,629/year of life saved (US$41,795, EU€58,629, GBP£32,001) and AU$77,889/quality-adjusted life year gained (US$55,526, EU€49,202, GBP£42,504). We have assumed a threshold of AU$50,000/quality-adjusted life year gained to suggest cost-effectiveness. At its current acquisition price, sacubitril-valsartan in comparison to enalapril is not likely to be cost-effective in the management of acute decompensated heart failure in Australia. A price reduction of more than 25% would confer cost-effectiveness.


Volumization of the Brow at the Time of Blepharoplasty: Treating the Eyebrow Fat Pad as an Independent Unit.
Loss of volume in the sub-brow fat pad with associated descent of the eyebrow is a common anatomical finding resulting in both functional and aesthetic consequences. A variety of techniques have been described to address brow position at the time of blepharoplasty. To our knowledge, none of these techniques treat the sub-brow fat pad as an isolated unit. Doing so enables the surgeon to stabilize and volumize the brow without resultant tension on the blepharoplasty wound. The authors describe a technique for addressing volume loss in the eyebrow with associated brow descent that treats the sub-brow fat pad as an isolated unit. A retrospective review of all patients undergoing brow ptosis repair by a single surgeon (J.W.S.) over an 11-month period was performed. Eighteen patients and 33 brows underwent the technique described. Patients were followed for an average of 11 weeks (range: 4 weeks to 20 weeks). All patients preoperatively displayed both visually significant dermatochalasis and brow descent below the orbital rim. Evaluation of pre- and postoperative photos demonstrates successful volumization of the brow with skin redraping without focal dimpling or undue tension on the eyelid wound. Performing a dissection that allows the sub-brow fat pad to be elevated in isolation from the overlying orbicularis and underlying periosteum allows for volumization and of the brow without compromising closure. This technique is a safe and effective means of volumizing the brow and treating secondary brow descent.


Theoretical modeling of molecules in weakly interacting environments: trifluoride anions in argon.
The properties of molecules can be affected by the presence of a host environment. Even in inert rare gas matrices such effects are observable, as for instance in matrix isolation spectroscopy. In this work we study the trifluoride anion in cryogenic argon environments. To investigate the structure and vibrational properties of the guest-host systems, a potential energy surface of compound F-3-argon structures is determined from ab initio calculations with the CCSD(T)-F12b approach. Argon environments are probed with minima hopping optimizations of extended trifluoride-argon clusters. The vibrations of F-3 within the optimized environments are examined with anharmonic vibrational analyses. Among the three identified structural surroundings for the trifluoride, two are characterized by relatively favorable guest-host and host-host interactions as well as vibrational zero-point energies. A striking dependence of the trifluoride properties on the particular argon environment reveals the delicate influence of the host atoms on the guest molecule. Very good agreement with measured data suggests that in experiment F-3 occupies a double-vacancy site.


Lumbosacral Plexopathy in Pelvic Injury - A Cause of Hip Instability in Acetabular Fractures: A Report of Two Cases.
Lumbosacral plexopathy is a rare clinical entity that results in potentially severe neurological deficit. The clinical presentation of lumbosacral plexopathy includes motor and sensory deficits. However to the best of our knowledge, hip instability secondary to lumbosacral plexopathy has not been reported in current literature. We report two cases of pelvic injury in which recurrent hip subluxation occurred following fixation of acetabular fractures. We attribute this to inadequate hip muscle tension from the associated lumbosacral plexopathy. In patients with acetabular fractures, this may lead to debilitating hip joint instability. In an already traumatized hip joint, this instability has a poor prognosis and can lead to degenerative changes with the eventual need for hip replacement.


Exosomes: Applications in Respiratory Infectious Diseases and Prospects for Coronavirus Disease 2019 (COVID-19).
Exosomes are small extracellular vesicles of 30-150 nm diameter secreted by almost all cells. In recent years, with continuous deeper understanding of exosomes physiological functions, different reports have proven that exosomes can facilitate cell-to-cell communication by binding to target cells and transferring their contents, together with RNAs, DNAs, proteins, and lipids between cells and tissues. With advantages that exosomes can be involved in various types of physiological processes, such as blood coagulation, cellular homeostasis, inflammation, immune surveillance, stem cell differentiation, neuroprotection, and tissue regeneration and angiogenesis. Exosomes have been demonstrated that they can be applied in identification and treatment of multiple disorders such as cancers, cerebral ischemia, and respiratory infectious diseases. Importantly, researchers utilize application of exosomes in the treatment of various respiratory infectious diseases that have made some breakthrough progress. However, with the global pandemic of Coronavirus Disease 2019 (COVID-19), we have focused on applications of exosomes in respiratory infectious diseases and their serious complications, including influenza, TB, ARDS and sepsis. In this review, we explain the use of exosomes in various respiratory infectious diseases and their serious complications, and hope to provide new ideas for the treatment of new coronavirus infections.


Prostaglandin-endoperoxide H synthase-2 expression and activity increases with term labor in human chorion.
We investigated the changes in prostaglandin-endoperoxide H synthase (PGHS) specific activity and the levels and distribution of PGHS-1 and PGHS-2 mRNA in chorion collected at term before the onset of labor (CS) and after term labor and delivery (SL). PGHS specific activity and PGHS-2 mRNA abundance were higher in chorion collected after SL compared with that obtained at CS (P < 0.001); there was no difference in the levels of PGHS-1 mRNA between CS and SI, tissues. The increase in PGHS specific activity at SL was significantly correlated with PGHS-2 mRNA expression (P < 0.05) but not with PGHS-1 mRNA levels. In situ hybridization indicated that the pervasiveness of staining for PGHS-1 mRNA throughout full-thickness membranes did not change with labor onset; however, a greater number of cells expressed PGHS-2 in SL tissues. Our results demonstrate a selective increase in PGHS-2 expression and activity in chorion trophoblasts and mesenchymal cells with term labor onset. These observations are similar to those concerning amnion and imply that a concerted mechanism may exist in the fetal membranes to induce PGHS-2 expression at labor.


[Pacemaker syndrome with AV-synchronized stimulation of the heart].
Characteristic signs of the pacemaker syndrome occurred in a 69-year-old woman with intermittent 3 degrees atrioventricular (AV) block after implantation of a dual-chamber AV-synchronized pacemaker. Cannon beats due to inappropriate atrial timing were the main haemodynamic finding. Their development and size depended on the programmed AV interval and AV-synchronized mode of stimulation. Very long AV intervals in the DDD mode at a heart rate of 100/min caused very unpleasant palpitations and pulsations in the upper thorax. The symptoms due to the cannon beats were avoided by changing to a short AV interval. The clinical and haemodynamic events were thus the consequence of preserved sinus node function with subsequent atrial triggering.


myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course.
44 small cell lung cancer cell lines established from 227 patients were studied for myc family DNA amplification (c-myc, N-myc, and L-myc). Two of 19 lines (11%) established from untreated patients' tumors had DNA amplification (one N-myc and one L-myc), compared with 11 of 25 (5 c-myc, 3 N-myc, and 3 L-myc) cell lines (44%) established from relapsed patients' tumors (P = 0.04). The 19 patients who had tumor cell lines established before chemotherapy treatment survived a median of 14 wk compared with 48 wk for the 123 extensive stage patients who did not have cell lines established (P less than 0.001). Relapsed patients whose cell lines had c-myc DNA amplification survived a shorter period (median of 33 wk) than patients whose cell lines did not have c-myc amplification (median of 53 wk; P = 0.04). We conclude that myc family DNA amplification is more common in tumor cell lines established from treated than untreated patients' tumors, and c-myc amplification in treated patients' tumor cell lines is associated with shortened survival.


A randomized controlled trial of cognitive-behavior therapy for tinnitus.
This study is a randomized, waitlist-controlled trial testing the effect of a brief, "manualized" cognitive-behavioral group therapy on distress associated with tinnitus, quality of well-being, psychological distress including depression, and internal focus. Cognitive-behavioral therapy (CBT) included training in activity planning, relaxation training and, primarily, cognitive restructuring. Sixty-five participants were recruited, and 41 completed treatment. Participants were randomly assigned to receive 8 weeks of manualized group CBT either immediately or after an 8-week waiting period. Participants completed outcome measures at the time of their random assignment and at 8, 16, and 52 weeks later. Repeated-measure analysis of covariance revealed significant group-by-time interactions on measures of tinnitus distress and depression, indicating that CBT led to greater improvement in those symptoms. The current results suggest that CBT, applied in a group format using a manual, can reduce the negative emotional distress, including depression, associated with tinnitus.


Increased sensitivity of a new commercial reverse transcriptase-quantitative PCR for the detection of Pneumocystis jirovecii in respiratory specimens.
Optimal sensitivity to detect low Pneumocystis loads is of importance to take individual and collective measures to avoid evolution towards Pneumocystis pneumonia and outbreaks in immunocompromised patients. This study compares two qPCR procedures, a new automated RTqPCR using the GeneLEAD VIII extractor/thermocycler (GLVIII; ∼2.2 h workflow) and a previously validated in-house qPCR assays (IH; ∼5 h workflow) both targeting mtSSU and mtLSU for detecting P. jirovecii in 213 respiratory samples. GLVIII was found to be more sensitive than IH, detecting eight more specimens. Bland-Altman analysis between the two procedures showed a Cq bias of 1.17 ± 0.07 in favor of GLVIII. The fungus Pneumocystis needs to be detected early in respiratory samples to prevent pneumonia in immunocompromised hosts. We evaluated a new commercial RTqPCR on 213 respiratory samples to detect Pneumocystis and found it more sensitive and faster than our routine sensitive in-house qPCR assay.


Adult nephrology fellowship training in the United States: trends and issues.
This article reviews trends and issues related to adult nephrology fellowship education in the United States. The number of nephrology fellowship programs and trainees has continued to increase slowly despite limitations in funding of graduate medical education. The use of the Electronic Residency Application System has provided information for the first time on the number, demographics, and behavior of applicants that can be used as baseline data for tracking trends in fellowship applications and for formulating training policies. Issues that nephrology training programs face are discussed in this review: (1) A more stringent graduate medical education regulatory environment, (2) the use of the National Resident Matching Program to enhance the nephrology fellowship applicant selection process, (3) future nephrology workforce shortages, and (4) the continued subspecialization of nephrology. By working together, nephrology fellowship programs can overcome barriers that are raised by these issues and improve the fellowship training experience.


Cellular transcription factors Sp1 and Sp3 suppress varicella-zoster virus origin-dependent DNA replication.
The varicella-zoster virus (VZV) origin of DNA replication (oriS) contains a 46-bp AT-rich palindrome and three consensus binding sites for the VZV origin binding protein (OBP) encoded by VZV ORF51. All three OBP binding sites are upstream of the palindrome in contrast to the sequence of the herpes simplex virus oriS, which has required OBP binding sites upstream and downstream of the AT-rich region. We are investigating the roles that sequences downstream of the palindrome play in VZV oriS-dependent DNA replication. Computer analysis identified two GC boxes, GC box 1 and GC box 2, in the downstream region which were predicted to be binding sites for the cellular transcription factor Sp1. Electrophoretic mobility shift assay and supershift assays showed that two members of the Sp family (Sp1 and Sp3) stably bind to GC box 1, but not to GC box 2. A predicted binding site for the cellular factor Yin Yang 1 (YY1) that overlaps with GC box 2 was also identified. Supershift and mutational analyses confirmed the binding of YY1 to this site. Mutation of GC box 1 resulted in loss of Sp1 and Sp3 binding and an increase in origin-dependent replication efficiency in DpnI replication assays. In contrast, mutation of the YY1 site had a statistically insignificant effect. These results suggest a model where origin-dependent DNA replication and viral transcription are coupled by the binding of Sp1 and Sp3 to the downstream region of the VZV replication origin during lytic infection. They may also have implications regarding establishment or reactivation of viral latency.


Activation of carcinogens and mutagens by rat colon mucosa.
Colon mucosal cells can catalyze the activation of precarcinogens to mutagenic metabolites without the intermediacy of intestinal bacteria as shown in a mutagenesis assay system composed of Salmonella typhimurium strain TA100 and the 9000 X g supernatant fraction of rat colon mucosal cells. Pretreatment of rats with beta-naphtoflavone increased the activation of 2-aminoanthracene 10- to 20-fold and the activation of benzo(a)pyrene 4-fold. Pretreatment of rats with Aroclor 1254 doubled the activation of 2-aminoanthracene over control but had no effect on the activation of benzo(a)pyrene. The activation of 2-aminoanthracene and benzo(a)pyrene by liver was induced significantly by pretreatment with beta-naphthoflavone and Aroclor 1254. Phenobarbital/hydrocortisone pretreatment did not increase the activation by the colon system of any precarcinogen tested but did increase the activation of 2-aminoanthracene, cyclophosphamide, and isophosphamide by the liver system. The activation of precarcinogens in the bacterial test system is directly correlated with the activities of the pretreated colon and liver preparations toward several drug and polycyclic hydrocarbon substrates assayed in vitro.


Crestal bone changes around titanium implants. A histometric evaluation of unloaded non-submerged and submerged implants in the canine mandible.
Today, implants are placed using both non-submerged and submerged approaches, and in 1- and 2-piece configurations. Previous work has demonstrated that peri-implant crestal bone reactions differ radiographically under such conditions and are dependent on a rough/smooth implant border in 1-piece implants and on the location of the interface (microgap) between the implant and abutment/restoration in 2-piece configurations. The purpose of this investigation was to examine histometrically crestal bone changes around unloaded non-submerged and submerged 1- and 2-piece titanium implants in a side-by-side comparison. A total of 59 titanium implants were randomly placed in edentulous mandibular areas of 5 foxhounds, forming 6 different implant subgroups (types A-F). In general, all implants had a relatively smooth, machined coronal portion as well as a rough, sandblasted and acid-etched (SLA) apical portion. Implant types A-C were placed in a non-submerged approach, while types D-F were inserted in a submerged fashion. Type A and B implants were 1-piece implants with the rough/smooth border (r/s) at the alveolar crest (type A) or 1.0 mm below (type B). Type C implants had an abutment placed at the time of surgery with the interface located at the bone crest level. In the submerged group, types D-F, the interface was located either at the bone crest level (type D), 1 mm above (type E), or 1 mm below (type F). Three months after implant placement, abutment connection was performed in the submerged implant groups. At 6 months, all animals were sacrificed. Non-decalcified histology was analyzed by evaluating peri-implant crestal bone levels. For types A and B, mean crestal bone levels were located adjacent (within 0.20 mm) to the rough/smooth border (r/s). For type C implants, the mean distance (+/- standard deviation) between the interface and the crestal bone level was 1.68 mm (+/- 0.19 mm) with an r/s border to first bone-to-implant contact (fBIC) of 0.39 mm (+/- 0.23 mm); for type D, 1.57 mm (+/- 0.22 mm) with an r/s border to fBIC of 0.28 mm (+/- 0.21 mm); for type E, 2.64 mm (+/- 0.24 mm) with an r/s border to fBIC of 0.06 mm (+/- 0.27 mm); and for type F, 1.25 mm (+/- 0.40 mm) with an r/s border to fBIC of 0.89 mm (+/- 0.41 mm). The location of a rough/smooth border on the surface of non-submerged 1-piece implants placed at the bone crest level or 1 mm below, respectively, determines the level of the fBIC. In all 2-piece implants, however, the location of the interface (microgap), when located at or below the alveolar crest, determines the amount of crestal bone resorption. If the same interface is located 1 mm coronal to the alveolar crest, the fBIC is located at the r/s border. These findings, as evaluated by non-decalcified histology under unloaded conditions, demonstrate that crestal bone changes occur during the early phase of healing after implant placement. Furthermore, these changes are dependent on the surface characteristics of the implant and the presence/absence as well as the location of an interface (microgap). Crestal bone changes were not dependent on the surgical technique (submerged or non-submerged).


Total body potassium and serum electrolyte concentrations in protein energy malnutrition.
The total body potassium (TBK) and serum electrolyte concentrations of malnourished children in Cape Town are similar to those in Jamaica. The TBK is almost always low and hyponatraemia is common, but there was no relationship between the TBK and serum Na and K concentrations. These abnormalities, particularly a very low TBK, appear to influence the prognosis. The expression of the observed TBK as a percentage of the expected value for a normal child, of the same weight and height, appears to be a useful index of the severity of the total body potassium deficit.


A systematic approach to obtain validated partial least square models for predicting lipoprotein subclasses from serum NMR spectra.
A systematic approach is described for building validated PLS models that predict cholesterol and triglyceride concentrations in lipoprotein subclasses in fasting serum from a normolipidemic, healthy population. The PLS models were built on diffusion-edited (1)H NMR spectra and calibrated on HPLC-derived lipoprotein subclasses. The PLS models were validated using an independent test set. In addition to total VLDL, LDL, and HDL lipoproteins, statistically significant PLS models were obtained for 13 subclasses, including 5 VLDLs (particle size 64-31.3 nm), 4 LDLs (particle size 28.6-20.7 nm) and 4 HDLs (particle size 13.5-9.8 nm). The best models were obtained for triglycerides in VLDL (0.82 < Q(2) <0.92) and HDL (0.69 < Q(2) <0.79) subclasses and for cholesterol in HDL subclasses (0.68 < Q(2) <0.96). Larger variations in the model performance were observed for triglycerides in LDL subclasses and cholesterol in VLDL and LDL subclasses. The potential of the NMR-PLS model was assessed by comparing the LPD of 52 subjects before and after a 4-week treatment with dietary supplements that were hypothesized to change blood lipids. The supplements induced significant (p < 0.001) changes on multiple subclasses, all of which clearly exceeded the prediction errors.


A Comparison of Resource Utilization in the Management of Anticholinergic Delirium Between Physostigmine and Nonantidote Therapy.
Background: Antimuscarinic delirium is associated with significant morbidity, and its management requires substantial resource allocation, including intubation, restraint, and intensive care unit (ICU) placement. There is controversy over the management of these patients. Physostigmine can rapidly reverse antimuscarinic delirium but has been associated with adverse effects. Objective: This study aims to assess the effect of physostigmine use on resource allocation and adverse events. Methods: This is a retrospective chart review of patients with an antimuscarinic toxidrome at a single hospital approved by the local institutional review board. A blinded abstractor recorded data from patient charts. Whether the patient was given physostigmine, intubated, restrained, or admitting to critical care was recorded. We recorded instances of seizure, vomiting, or bradycardia. The primary aim was to compare frequency of intubation as a function of physostigmine administration. Results: A total of 141 patients were identified. We found no difference between the groups in age, gender, or initial heart rate; 65 (46%) were given physostigmine, 45 (32%) were admitted to the ICU, and 29 (20%) were intubated. Patients who received physostigmine in the first 24 hours were less likely to be intubated and less likely to be admitted to an ICU. The instance of bradycardia (n = 16), vomiting (n = 27), and seizures (n = 7) was limited, and there were no significant differences between the groups. There were no associations noted between physostigmine administration and adverse effects. Conclusion and Relevance: This study demonstrated that physostigmine use is associated with decreased resource utilization (including intubation and ICU placement) without increasing rates of bradycardia, vomiting, or seizures.


[Breast feeding in Puerto Rico: traditional patterns, national trends and future strategies].
The Puerto Rican society has gone through profound transformations during the past 50 years. Industrialization and the incorporation of women into the labor force have been accompanied by medicalization of the reproductive process and a progressive reduction in the prevalence of breastfeeding as the cultural norm for nutrition of infants. The data base for 1990 places Puerto Rico significantly below Latin America and the United States in the percentage of breastfed infants. The authors report their experience in the promotion of breastfeeding during the last 5 years. The principal negative factors which hinder the beginning and maintenance of successful breastfeeding are of a social nature. The orientation of physicians towards technology underrates the benefits of breastfeeding. The marketing strategies of the corporations which manufacture artificial milk continuously violate the International Code for Marketing of Breast Milk Substitutes and disfigure the community's perception on the benefits of breastfeeding. The lack of social and legal support for the breastfeeding working mother frequently prevents her from carrying out successful breastfeeding for the recommended period of time. Strategies are presented for the overturn of the existent barriers which have reduced breastfeeding in Puerto Rico to the present precarious levels.


2'-Deoxyribonucleoside 5'-triphosphates bearing 4-phenyl and 4-pyrimidinyl imidazoles as DNA polymerase substrates.
We developed a versatile access to a series of 4-substituted imidazole 2'-deoxynucleoside triphosphate bearing functionalized phenyl or pyrimidinyl rings. 4-Iodo-1H-imidazole was enzymatically converted into the corresponding 2'-deoxynucleoside, which was then chemically derived into its 5'-triphosphate, followed by 4-arylation via Suzuki-Miyaura coupling using (hetero)arylboronic acids. Both KF (exo-) and Deep Vent (exo-) DNA polymerases incorporated these modified nucleotides in primer-extension assays, adenine being the preferred pairing partner in the template. The 4-(3-aminophenyl)imidazole derivative (3APh) was the most efficiently inserted opposite A by KF (exo-) with only a 37-fold lower efficiency (Vmax/KM) than that of the correct dTTP. No further extension occurred after the incorporation of a single aryl-imidazole nucleotide. Interestingly, the aryl-imidazole dNTPs were found to undergo successive incorporation by calf thymus terminal deoxynucleotidyl transferase with different tailing efficiencies among this series and with a marked preference for 2APyr polymerization.


[Benign positional paroxysmal vertigo in the general ear, nose, and throat clinic].
Benign positional paroxysmal vertigo is a common disease which may be caused by abnormal movement of utricular debris in the posterior semicircular canal. It is diagnosed by the Dix-Hallpike positional maneuver eliciting vertigo and nystagmus. Treatment generally consists of physical exercises with the Epley or Semont maneuvers. We review 43 consecutive patients diagnosed as BPPV in the last year and treated with physical therapy (Epley maneuvers). Results were very good, with a cure rate of 88.37% (53.5% after a single maneuver). Physical therapy is an effective treatment for BPPV.


[Therapy of Helicobacter pylori infection: "Who to treat, how to treat?"].
Seventeen years after detection of Helicobacter pylori as the pathogenetic factor in a variety of gastroduodenal diseases, current treatment options are about 90% effective in eradicating the bacteria and thereby curing the affiliated disorders. In 1987 successful therapy has been shown to reduce relapse rates of duodenal and gastric ulcers dramatically and clinicians all over the world started to perform a still ongoing vast number of trials searching for the most effective first--and in case of failure, second line-treatment options. The results of these trials led to strictly evidence based and generally accepted guidelines formulated by Consensus Reports. The main questions "who to treat" and "how to treat" can be answered by using the categories "strongly recommended indications", "advisable indications" that leave some space for individual decisions, and consideration of first and second time eradication therapies together as a package. Treatment has become simple: three drugs, twice daily for one week. All available protone pump inhibitors (PPI) have been shown to be effective and presently there is only a few antibiotic agents used in combination and defined dose, proven to ensure treatment success. The future will encounter clinicians with problems concerning patient compliance, antibiotic resistance and more effective second and even third line therapies. This paper will focus on two subjects: indications ("who to treat") and evidence-based eradication regimens ("how to treat") in a reasonable setting close to everyday clinical practice.


NeuN As a Neuronal Nuclear Antigen and Neuron Differentiation Marker.
The NeuN protein is localized in nuclei and perinuclear cytoplasm of most of the neurons in the central nervous system of mammals. Monoclonal antibodies to the NeuN protein have been actively used in the immunohistochemical research of neuronal differentiation to assess the functional state of neurons in norm and pathology for more than 20 years. Recently, NeuN antibodies have begun to be applied in the differential morphological diagnosis of cancer. However, the structure of the protein, which can be revealed by antibodies to NeuN, remained unknown until recently, and the functions of the protein are still not fully clear. In the present mini-review, data on NeuN accumulated so far are summarized and analyzed. Data on the structure and properties of the protein, its isoforms, intracellular localization, and hypothesized functions are reported. The application field of immunocytochemical detection of NeuN in scientific and clinical studies, as well as the difficulties in the interpretation of the obtained experimental data and their possible causes, is described in details.


Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era.
The development of cardiovascular disease (CVD) in long-term survivors of lymphoma is of increasing importance. Here, we characterize the cumulative incidence and risk factors for CVD in lymphoma patients diagnosed in the current treatment era. From 2002-2015, newly diagnosed lymphoma patients (>18 years) were enrollment into a prospective cohort study that captured incident CVD, consisting of congestive heart failure (CHF), acute coronary syndrome (ACS), valvular heart disease (VHD), and arrhythmia. The cumulative incidence of CVD was calculated with death modeled as a competing risk. We estimated the association of treatment with anthracyclines or radiotherapy and traditional CVD risk factors with incidence of CVD using hazard ratios (HR) and 95% confidence intervals (CI) estimated from Cox regression. After excluding prevalent CVD at lymphoma diagnosis, the study consisted of 3063 patients with a median age of 59 years (range 18-95). The cumulative incidence of CVD at 10-years was 10.7% (95% CI, 9.5%-12.1%). In multivariable analysis, increasing age (HR = 1.05 per year, p < 0.001), male sex (HR = 1.36, p = 0.02), current smoker (HR = 2.10, p < 0.001), BMI > 30 kg/m2 (HR = 1.45, p = 0.01), and any anthracycline treatment (HR = 1.57, p < 0.001) were all significantly associated with risk of CVD. Anthracyclines were associated with increased risk of CHF (HR = 2.71, p < 0.001) and arrhythmia (HR = 1.61, p < 0.01), but not VHD (HR = 0.84, p = 0.58) or ACS (HR = 1.32, p = 0.24) after adjustment for CVD risk factors. Even in the modern treatment era, CVD remains common in lymphoma survivors and preventive efforts are required that address both treatment and CVD risk factors.


Photoactive Zn-air batteries using spinel-type cobalt oxide as a bifunctional photocatalyst at the air cathode.
Spinel-type cobalt oxide (Co3O4) was synthesized and used as a photoactive bifunctional electrocatalyst towards the oxygen evolution reaction (OER) and the oxygen reduction reaction (ORR) at the air cathode of zinc-air batteries (ZABs). The Co3O4 having direct and indirect band gap energies of ca. 2.20 eV and ca. 1.35 eV can absorb visible light, generating photogenerated carriers and photoelectrons via the photoelectric effect. Upon exposure to visible light, the Co3O4 electrode exhibits ca. 30% higher current density than that under dark conditions and provides around 10-20% lower OER and ORR overpotentials than those under the dark conditions. Under visible light, the specific capacity of the as-fabricated photoactive ZAB cell is improved by ca. 10% as compared to that under dark conditions.


Modification of the existing maximum residue levels for acetamiprid in various crops.
In accordance with Article 6 of Regulation (EC) No 396/2005, the applicants Nisso Chemical Europe GmbH and Sipcam Italia S.p.A. submitted requests to the competent national authority in the Netherlands and in Italy, respectively, to modify the existing maximum residue levels (MRLs) for the active substance acetamiprid in various crops. The data submitted in support of these requests were found to be sufficient to derive MRL proposals for plums, aubergines, peppers, cucumbers, courgettes, other cucurbits with edible peel, poppy seeds, mustard seeds, pomegranates and honey. Adequate analytical methods for enforcement are available to control the residues of acetamiprid in the commodities under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of acetamiprid according to the reported agricultural practices is unlikely to present a risk to consumer health.


The circumstances surrounding the death of 105 elders as a result of resident-to-resident incidents in dementia in long-term care homes.
Resident-to-resident incidents in dementia in long-term care homes resulting in deaths represent a growing concern among residents, family members, care providers, care advocacy organizations, and policy makers. Despite these concerns and experts' predictions by which injurious and fatal incidents will increase in the coming years due to the projected growth in the number of people with dementia, no studies have been conducted in North America on these fatal incidents. This exploratory pilot study makes first steps towards bridging this major gap in research and practice. Using publicly available information (primarily newspaper articles and death review reports), practically useful patterns were identified pertaining to the circumstances surrounding the death of 105 elders as a result of these incidents. The findings could inform various efforts to prevent future deaths in similar circumstances, keep vulnerable and frail residents safe, and encourage researchers to examine risk and protective factors for these incidents.


MRI Evaluation of the Normal and Abnormal Endolymphatic Duct in the Pediatric Population: A Comparison with High-Resolution CT.
An enlarged vestibular aqueduct is the most commonly reported imaging abnormality in children with sensorineural hearing loss. MR imaging is often used to evaluate pediatric sensorineural hearing loss; however, there are no well-established size criteria on MR imaging to diagnose an enlarged endolymphatic duct. The first purpose of the study was to determine a range of normal endolymphatic duct sizes on MR imaging and compare it with that in high-resolution CT. The second purpose was to assess the sensitivity and specificity of MR imaging in diagnosing an enlarged endolymphatic duct in patients with an enlarged vestibular aqueduct on CT. Endolymphatic duct midaperture measurements were analyzed in 52 patients with no history of sensorineural hearing loss. Comparison of CT and MR imaging was made in a second cohort of 41 patients with a normal midaperture width on CT. The sensitivity and specificity of MR imaging were then evaluated in a third cohort of 24 patients with a documented enlarged vestibular aqueduct on CT. In 94 ears, normal endolymphatic duct midaperture measurements ranged from 0 to 0.9 mm on MR imaging. A significant correlation (P <.001) and moderate agreement were found between CT and MR imaging in 81 ears with a normal vestibular aqueduct on CT. Twenty-four patients had bilateral (n = 14) or unilateral (n = 10) enlarged vestibular aqueducts on CT, and the sensitivity and specificity of MR imaging were 97% and 100%, respectively, for a diagnosis of an enlarged endolymphatic duct. MR imaging measurements of the normal endolymphatic duct are similar to those established for CT. MR imaging is a useful tool for the diagnosis of enlarged vestibular aqueduct.


pH-Dependent absorption spectrum of oxyluciferin analogues in the active site of firefly luciferase.
In the quest for the identification of the light emitter(s) responsible for the firefly bioluminescence, the study of oxyluciferin analogues with controlled chemical and electronic structures is of particular importance. In this article, we report the results of our experimental and computational investigation of the pH-dependent absorption spectra characterizing three analogues bound into the luciferase cavity, together with adenosine-monophosphate (AMP). While the analogue microscopic pKa values do not differ much from their reference values, it turns out that the AMP protonation state is analogue-dependent and never doubly-deprotonated. A careful analysis of the interactions evidences the main role of E344 glutamic acid, as well as the flexibility of the cavity which can accommodate any oxyluciferin analogue. The consideration of the absorption spectra suggests that the oxyluciferin enolate form has to be excluded from the list of the bioluminescence reaction products.


Postmortem parietal cortex TPH2 expression is not altered in schizophrenic, unipolar-depressed, and bipolar patients vs control subjects.
Serotonin (5-hydroxytryptamine [5-HT]) is a neurotransmitter synthesized in the raphe nuclei of the brain stem in the central nervous system (CNS) and also in the periphery. Dysfunction of the serotonergic system has been implicated in the pathogenesis of psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. For more than a decade, only one gene encoding TPH was identified in vertebrates. Recently, a second TPH gene, designated TPH2, was detected, located on human chromosome 12, a susceptibility region for affective disorders. TPH2 is predominantly expressed in the brain, whereas the classical TPH gene, TPH1, is expressed in peripheral tissues. The discovery of the brain-abundant TPH2 gene justifies a new concept of the CNS serotonergic system. TPH2, rather than TPH1, has now become a candidate gene for 5-HT-related affective disorders. We compared TPH2 mRNA levels in postmortem parietal cortex of unipolar-depressed, bipolar, and schizophrenic patients vs control subjects, using real-time reverse transcription polymerase chain reaction. No significant difference in TPH2 mRNA levels was found among the four diagnostic groups. The lack of difference might suggest that this gene is not involved in the etiology of of these psychiatric disorders. Alternatively, it is possible that the parietal cortex is not the relevant brain area involved in the pathophysiology of these disorders or that posttranscriptional modifications of TPH2 mRNA occur in these patients, causing changes in protein levels and/or enzymatic activity.


Accurate in vitro splicing of human beta-globin RNA.
Human beta-globin RNA transcribed from an exogenous DNA template is spliced in vitro by concentrated whole cell extracts from HeLa cells. Using the primer extension technique, we have shown that the small intervening sequence is spliced accurately and that the sequence of the product across the splice junction is identical to that of beta-globin mRNA prepared from human reticulocytes. The efficiency of the splicing reaction is low. The RNA transcript containing both introns and terminated upstream from the polyadenylation site is spliced most efficiently. The transcript which is terminated downstream from the polyadenylation site is not spliced at all. Thalassemic beta-globin RNA which carries an extra splice site in the small intron is also spliced, albeit with a low yield.


[Morphofunctional properties of the blood cells in patients with ischemic heart disease following gravitational correction].
Red cell and platelet surface membranes, platelet adhesion to glass were examined in coronary patients treated among other treatment modalities with gravitation surgical correction of the blood. Scanning electron microscopy was used in the study. The studies revealed the minimal injurious effect of the extracorporeal contour on blood cells; a manifest improvement of cellular morphology and function was observed after a course of procedures. An attempt was made to assess the mechanism of gravitation surgery effect on blood cells.


Assessment of health awareness and knowledge toward SARS-CoV-2 and COVID-19 vaccines among residents of Makkah, Saudi Arabia.
Public awareness regarding COVID-19 plays an important role in controlling the virus' spread and treating infected people. A high level of awareness among the public will help to implement preventive measures, particularly in the most populated regions, such as Makkah, Saudi Arabia. COVID-19 is an infectious disease and the Saudi Arabian government has taken serious precautions and implemented several preventive measures. In addition, The Ministry of Health (MOH) has launched many awareness campaigns and provided COVID-19 vaccines for free. To assess the Public's level of health awareness and knowledge toward SARS-CoV-2 and COVID-19 vaccines among residents of Makkah, Saudi Arabia. A cross-sectional study was conducted in the Makkah region from February 23 to March 2, 2021. The questionnaire was generated using a Google form and distributed online through social platforms such as Twitter and WhatsApp. The questionnaire consisted of five sections and six hundred participants have answered and completed all questions. Then, All data were imported into Microsoft Excel and analyzed using the statistical tools SAS version 9.4 and SPSS version 25 software. A total of 600 participants from the Makkah region were found to have a high level of awareness and knowledge about all aspects of SARS-CoV-2 and the COVID-19 disease. For example, all participants considered coronavirus to be contagious, and 89.8% of them knew that COVID-19's symptoms are similar to those of seasonal flu. Most respondents showed a high level of awareness regarding the main factors of SARS-CoV-2 transmission. Over 98.7% of respondents were aware of the role of gatherings and events in further spread of the virus. The participants showed a good level of awareness about other preventive measures, such as maintaining social distancing and wearing a mask. However, the respondents considered COVID-19 vaccines to be effective, but some of them were not aware of their side effects, and 38.8% planned to receive a vaccine. The residents of Makkah showed a high level of awareness about these aspects; an excellent awareness level was noted for SARS-CoV-2, means of transmission, disease symptoms and prevention of viral spread. On the other hand, the participants had less knowledge regarding COVID-19 vaccines; hence, more effort is required to educate people about the safety and benefits of the vaccines.


3,4-Dihydroxy-7,8-dihydro-beta-ionone 3-O-beta-D-glucopyranoside and other glycosidic constituents from apple leaves.
3,4-Dihydroxy-7,8-dihydro-beta-ionone 3-O-beta-D-glucopyranoside 1 has been isolated from a methanolic extract of apple (Malus domestica) leaves by XAD-2 adsorption chromatography and subsequent purification by high speed countercurrent chromatography (HSCCC) and HPLC. Under acidic conditions this glycoside gives rise to a number of volatile compounds including 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN) 2, which is known as an off-flavor compound in wine. In the course of the study, six additional glycoconjugates were isolated from apple leaves, i.e. roseoside 3, 3-oxo-alpha-ionol beta-D-glucopyranoside 4, benzoic acid beta-D-glucose ester 5, kaempferol 3-O-rhamnoside 6, (+)-syringaresinol beta-D-glucopyranoside 7 and 4-hydroxy-5-(3''-methyl-2''-butenyl)-benzoic acid methylester 3-beta-D-glucopyranoside 8. The latter compound has been isolated for the first time in nature. In order to avoid the 'kerosene-off-flavor' caused by TDN, the methanolic extract has been subjected to yeast fermentation. This treatment reduced the amount of TDN formed and resulted in an improved flavor impression of the methanolic extract.


Suppression of plasma renin activity by indomethacin in man.
The effect of indomethacin or placebo on aldosterone, plasma renin activity (PRA), sodium excretion, and urinary prostaglandin (PG) levels was investigated in five hypertensive subjects in 100 mEq sodium balance who had experienced malignant hypertension with a disturbance of their renin-aldosterone relationship in the past. Indomethacin significantly lowered aldosterone levels by 43%, PRA by 58%, 24-hour sodium excretion by 49%, and urinary PG excretion, an indicator of renal PG synthesis, by 67%. Angiotensin infusion increased aldosterone to the same level before and after treatment with indomethacin. Similarly, in normal subjects in 150 mEq sodium balance, indomethacin lowered PRA by 47%; sodium excretion fell by 33%, and urinary prostaglandin E (PGE) excretion, by 55%. The acute elevation in PRA 10 minutes after intravenous furosemide was completely abolished by indomethacin. Five subjects with essential hypertension were classified as normal renin hypertensives according to their response to orally administered furosemide. Indomethacin pretreatment resulted in 60% reduction of PRA following furosemide, and three of these subjects now fell into the low renin category. Studies in vitro demonstrated that indomethacin has no effect on the renin-renin substrate interaction. Thus, indomethacin lowers PRA concomitantly with a reduction in renal PG synthetase activity. Whether indomethacin inhibits renin release by an intrarenal, PG-related mechanism or secondarily via sodium retention is discussed.


Teaching palliative care to critical care medicine trainees.
Palliative care is an important component of critical care medicine. Few fellowship programs have developed a curriculum designed to teach palliative care precepts to trainees. We describe our 2-yr experience in teaching palliative care to multidisciplinary critical care medicine fellows. Two-consecutive-year palliative care training for unselected critical care medicine fellows at a large, urban, university, tertiary care medical center. We 1) identified palliative care skills and knowledge that first-year critical care fellows should acquire; 2) developed a curriculum to teach those skills and knowledge, including required readings, small group lectures and skills sessions that included role-playing to modify skills and attitudes, and (in year 2) experiential learning on a hospital-based palliative care rotation; and 3) attempted to evaluate the curriculum with attitude and knowledge assessments. A total of 35 fellows participated in the palliative care training during the 2 yrs reported. Seven fellows participated in a clinical rotation in palliative care. Fellows evaluated usefulness of the small group sessions between 4.4 and 4.9 on a 5-point Likert scale. Four of seven fellows rated the clinical rotation quality at 3/5. Pretest and posttest knowledge mean scores were 58% and 69%, respectively. Problems included providing time for fellows to participate in the clinical rotation and negative attitudes regarding the relevance of palliative care to their future in critical care. Palliative care training for critical care fellows is feasible. Fellows value skills training more than a clinical rotation in palliative care. Baseline knowledge of palliative care is low.


Alsactide: ACTH-agonist for use in microdoses in brain-adrenal and other feedsidewards.
An increasing number of ACTH-related peptides have been isolated and/or chemically synthesized. In addition to the multiplicity of molecules, there is experimental evidence for multiple target cells and multiple receptors, and hence for different biological activities. The heptadecapeptide analogue alsactide (ACTH 1-17: Synchrodyn) has a C-terminal amide group (butylamide) and the substitution of beta-alanine for serine in position 1 and of lysine for arginine in position 17. These modifications account for enhanced biological activity and uniquely demonstrated chronopharmacological properties. In adult healthy men, the tailoring of dosage and timing of peptide administration was successful in a selective and transient stimulation of glucocorticoid secretion, without a change in the plasma concentrations of aldosterone and testosterone. The dose of 10 micrograms alsactide injected subcutaneously at awakening is proposed for clinical application with the aim of enhancing cortisol secretion in diurnally active subjects. It is noteworthy that injection of even much higher doses for several days at this particular circadian stage did not elicit detectable antibodies to the peptide in more than 200 patients. Restoring or reinforcing the circadian ordering of bioperiodicities correlated with the adrenocortical cycle can thus be achieved as a result of a time-specified therapy with an ACTH-agonist analogue. The results of studies in experimental animals and of preliminary trials in human beings have emphasized the value of alsactide as the first chronizer-peptide in clinical medicine. Its use in the dosage here proposed is expected to be beneficial for preventing deterioration of the circadian system in the elderly, for enhancing psycho-physical performances, and for gaining compliance with regard to chronic disease as well as tolerance to a number of potentially damaging xenobiotics.


Mutation of archaeal isopentenyl phosphate kinase highlights mechanism and guides phosphorylation of additional isoprenoid monophosphates.
The biosynthesis of isopentenyl diphosphate (IPP) from either the mevalonate (MVA) or the 1-deoxy-d-xylulose 5-phosphate (DXP) pathway provides the key metabolite for primary and secondary isoprenoid biosynthesis. Isoprenoid metabolism plays crucial roles in membrane stability, steroid biosynthesis, vitamin production, protein localization, defense and communication, photoprotection, sugar transport, and glycoprotein biosynthesis. Recently, an alternative branch of the MVA pathway was discovered in the archaeon Methanocaldococcus jannaschii involving a small molecule kinase, isopentenyl phosphate kinase (IPK). IPK belongs to the amino acid kinase (AAK) superfamily. In vitro, IPK phosphorylates isopentenyl monophosphate (IP) in an ATP and Mg(2+)-dependent reaction producing IPP. Here, we describe crystal structures of IPK from M. jannaschii refined to nominal resolutions of 2.0-2.8 A. Notably, an active site histidine residue (His60) forms a hydrogen bond with the terminal phosphate of both substrate and product. This His residue serves as a marker for a subset of the AAK family that catalyzes phosphorylation of phosphate or phosphonate functional groups; the larger family includes carboxyl-directed kinases, which lack this active site residue. Using steady-state kinetic analysis of H60A, H60N, and H60Q mutants, the protonated form of the Nepsilon(2) nitrogen of His60 was shown to be essential for catalysis, most likely through hydrogen bond stabilization of the transition state accompanying transphosphorylation. Moreover, the structures served as the starting point for the engineering of IPK mutants capable of the chemoenzymatic synthesis of longer chain isoprenoid diphosphates from monophosphate precursors.


Achieving clinical excellence through evidence-based practice: report of an educational initiative.
We live in a political and professional climate which requires us to define, maintain and seek to improve the quality of all aspects of health care practice, not least via underpinning decisions and actions with robust evidence. In order to meet this challenge, staff must be clinically competent, reflective about their practice, committed to delivering a 'First Class Service' and able to work in a truly multidisciplinary way (as opposed to the unidisciplinary model frequently seen in operation). In addition, they need to be research 'literate' and able to contribute positively to the management and sustainment of planned change. For managers, the role of staff development in order to meet these goals is not inconsiderable. This paper discusses the process and outcomes of a successful educational initiative which sought to meet the plethora of challenges that face managers and their staff in the course of trying to achieve these goals.


The role of chemisorbed hydroxyl species in alkaline electrocatalysis of glycerol on gold.
The mechanism of energy conversion in a direct glycerol fuel cell (DGFC) is governed by the anode supported heterogeneous steps of glycerol electro-oxidation. In aerated alkaline electrolytes, glycerol also participates in a base catalyzed process, which can release certain species mixing with the anode catalyzed surface products. As a result, selective probing of the surface catalytic reactions involving such systems can be difficult. The present work addresses this issue for a gold anode by using the analytical capability of cyclic voltammetry (CV). In addition, surface plasmon resonance measurements are used to optically probe the adsorption characteristics of the electrolyte species. The net exchange current of the oxidation process and the transfer coefficient of the rate determining step are evaluated by analyzing the CV data. The interfacial reactions and their products on Au are identified by measuring the number of electrons released during the electro-oxidation of glycerol. The results indicate that these reactions are facilitated by the surface bound hydroxyl species on Au (chemisorbed OH(-) and faradaically formed Au-OH). By comparing the findings for stationary and rotating electrodes, it is shown that, convective mass transport is critical to maintaining efficient progression of the consecutive oxidation steps of glycerol. In the absence of hydrodynamic support, the main surface products of glycerol oxidation appear to be glyceraldehyde, glycerate and malonate, formed through a net six-electron route. In the presence of controlled convection, a ten-electron process is activated, where mesaxolate is the likely additional product.


Stability of Feline Coronavirus in aerosols and dried in organic matrices on surfaces at various environmental conditions.
Enveloped respiratory viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can be transmitted through aerosols and contact with contaminated surfaces. The stability of these viruses outside the host significantly impacts their transmission dynamics and the spread of diseases. In this study, we investigated the tenacity of Feline Coronavirus (FCoV) in aerosols and on surfaces under varying environmental conditions. We found that airborne FCoV showed different stability depending on relative humidity (RH), with higher stability observed at low and high RH. Medium RH conditions (50-60%) were associated with increased loss of infectivity. Furthermore, FCoV remained infectious in the airborne state over 7 h. On stainless-steel surfaces, FCoV remained infectious for several months, with stability influenced by organic material and temperature. The presence of yeast extract and a temperature of 4 °C resulted in the longest maintenance of infectivity, with a 5 log10 reduction of the initial concentration after 167 days. At 20 °C, this reduction was achieved after 19 days. These findings highlight the potential risk of aerosol and contact transmission of respiratory viruses, especially in enclosed environments, over extended periods. Studying surrogate viruses like FCoV provides important insights into the behavior of zoonotic viruses like SARS-CoV-2 in the environment.


Constitutive activation of TCR signaling molecules in IL-2-independent Herpesvirus saimiri-transformed T cells.
Both human T cell leukemia virus type I and simian Herpesvirus saimiri (HVS) transform human T cells in vitro. Although IL-2-independent growth in human T cell leukemia virus type I-transformed T cells is associated with constitutive phosphorylation of JAK/STAT kinases, we now demonstrate that different mechanisms may be responsible for the ability of HVS-transformed T cells to proliferate in the absence of exogenous cytokines. The IL-2 independence of an HVS-transformed cell line correlated with constitutive activation of protein tyrosine kinases known to be induced following TCR engagement. Thus, in these cells we observed increased phosphotransferase activity of Lck as well as constitutive tyrosine phosphorylation of the TCR-associated ZAP-70 kinase and expression of the related Syk protein tyrosine kinase. While Syk is generally not expressed in activated T cells, its introduction has been shown to enhance TCR responsiveness. These results suggest that distinct signal transduction cascades can participate in the transition of T cells to IL-2 independence.


First-episode medication-naive major depressive disorder is associated with altered resting brain function in the affective network.
Major depressive disorder (MDD) has been associated with abnormal structure and function of the brain's affective network, including the amygdala and orbitofrontal cortex (OFC). However, it is unclear if alterations of resting-state function in this affective network are present at the initial onset of MDD. To examine resting-state function of the brain's affective network in first-episode, medication-naive patients with MDD compared to healthy controls (HCs). Resting-state functional magnetic resonance imaging (rs-fMRI) was performed on 32 first-episode, medication-naive young adult patients with MDD and 35 matched HCs. The amplitude of low-frequency fluctuations (ALFF) of the blood oxygen level-dependent (BOLD) signal and amygdala-seeded functional connectivity (FC) were investigated. Compared to HC, MDD patients showed reduced ALFF in the bilateral OFC and increased ALFF in the bilateral temporal lobe extending to the insular and left fusiform cortices. Enhanced anti-correlation of activity between the left amygdala seed and the left OFC was found in MDD patients but not in HCs. Reduced ALFF in the OFC suggests hypo-functioning of emotion regulation in the affective network. Enhanced anti-correlation of activity between the amygdala and OFC may reflect dysfunction of the amygdala-OFC network and additionally represent a pathological process of MDD.


Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5'-monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by loop 6.
The conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP) is the committed and rate-limiting reaction in de novo guanine nucleotide biosynthesis. Inosine 5'- monophosphate dehydrogenase (IMPDH) is the enzyme that catalyzes the oxidation of IMP to XMP with the concomitant reduction of nicotinamide adenine dinucleotide (from NAD(+) to NADH). Because of its critical role in purine biosynthesis, IMPDH is a drug design target for anticancer, antiinfective, and immunosuppressive chemotherapy. We have determined the crystal structure of IMPDH from Borrelia burgdorferi, the bacterial spirochete that causes Lyme disease, with a sulfate ion bound in the IMP phosphate binding site. This is the first structure of IMPDH in the absence of substrate or cofactor where the active-site loop (loop 6), which contains the essential catalytic residue Cys 229, is clearly defined in the electron density. We report that a seven residue region of loop 6, including Cys229, is tilted more than 6 A away from its position in substrate- or substrate analogue-bound structures of IMPDH, suggestive of a conformational change. The location of this loop between beta6 and alpha6 links IMPDH to a family of beta/alpha barrel enzymes known to utilize this loop as a functional lid during catalysis. Least-squares minimization, root-mean-square deviation analysis, and inspection of the molecular surface of the loop 6 region in the substrate-free B. burgdorferi IMPDH and XMP-bound Chinese hamster IMPDH show that loop 6 follows a similar pattern of hinged rigid-body motion and indicates that IMPDH may be using loop 6 to bind and sequester substrate and to recruit an essential catalytic residue.


Recent progress in gene therapy for Parkinson's disease.
Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD.


Different Polymorphisms of Vascular Endothelial Growth Factor Gene in Patients with Pre-Eclampsia among The Iranian Women Population.
Pre-eclampsia (PE) is a pregnancy complication and one of the leading causes of maternal and neonatal morbidity and mortality in the world. PE is characterized by high blood pressure and signs of damage to the other organs, most often the liver and kidneys. Given the importance of mutation in the vascular endothelial growth factor (VEGF) gene and its correlation with the incidence of PE, the relationship of VEGF encoding gene polymorphisms rs922583280, rs3025040 and rs10434 with the incidence of PE in the population of Iranian women was studied, in this research. In this case-control study, 100 pregnant women with PE diagnosis and 50 healthy pregnant women were evaluated using Sanger sequencing method to determine genotypes rs922583280, rs3025040 and rs10434. There was no significant difference in the allele frequency of rs922583280 and rs3025040 polymorphisms between case and control groups (P>0.05), while frequency of the recessive allele (G) for rs10434 polymorphism was significantly higher in the case group compared to the control group (P=0.014, case=24%, control=12%). Frequency of the allele A in the control group was higher than the patient group (case=76%, control=88%). Frequency of AG genotype in the patient group was also higher than the control group. In addition, frequency of AA genotype in the control group was higher than the patient group (case=57%, control=78). The results of this study demonstrated a significant difference between patient and control groups for the VEGF coding gene polymorphism rs10434 and it can affect the incidence of PE among Iranian women.


Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions.
The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclin-dependent kinase inhibitor flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of nuclear factor-kappaB (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from flavopiridol/vorinostat-mediated mitochondrial injury at 48 h, but both did not significantly restored clonogenic potential. Flavopiridol/vorinostat-mediated transcriptional repression of XIAP, Mcl-1-enhanced apoptosis, and loss of clonogenic potential also occurred in primary acute myelogenous leukemia (AML) blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by flavopiridol/vorinostat contributes functionally to apoptosis induction at early exposure intervals and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials.


Gene expression in the rhesus monkey endometrium: differential display and laser capture microdissection.
The primate endometrium is a complex heterogeneous tissue that requires proper maturation to achieve a hospitable environment for implantation. Endometrial differentiation and maturation is primarily controlled through the action of progesterone during the secretory phase. Many of the genes and gene networks that are involved in this process are likely to be induced or inhibited in a temporal, spatial, and cell-type specific context within the endometrium. We have used several approaches to address these latter issues in the rhesus monkey endometrium. The use of differential display with hormonally distinct endometrial cDNA populations prepared from artificially controlled menstrual cycles has allowed us to identify different P-dependent mRNA regulatory patterns during simulated secretory phases. In addition, we have coupled differential display with laser capture microdissection to further study region and cell-type specific changes in the primate endometrium.


Finite-element analysis of microwave scattering from a three-dimensional human head model for brain stroke detection.
In this paper, a detailed analysis of microwave (MW) scattering from a three-dimensional (3D) anthropomorphic human head model is presented. It is the first time that the finite-element method (FEM) has been deployed to study the MW scattering phenomenon of a 3D realistic head model for brain stroke detection. A major contribution of this paper is to add anatomically more realistic details to the human head model compared with the literature available to date. Using the MRI database, a 3D numerical head model was developed and segmented into 21 different types through a novel tissue-mapping scheme and a mixed-model approach. The heterogeneous and frequency-dispersive dielectric properties were assigned to brain tissues using the same mapping technique. To mimic the simulation set-up, an eight-elements antenna array around the head model was designed using dipole antennae. Two types of brain stroke (haemorrhagic and ischaemic) at various locations inside the head model were then analysed for possible detection and classification. The transmitted and backscattered signals were calculated by finding out the solution of the Helmholtz wave equation in the frequency domain using the FEM. FE mesh convergence analysis for electric field values and comparison between different types of iterative solver were also performed to obtain error-free results in minimal computational time. At the end, specific absorption rate analysis was conducted to examine the ionization effects of MW signals to a 3D human head model. Through computer simulations, it is foreseen that MW imaging may efficiently be exploited to locate and differentiate two types of brain stroke by detecting abnormal tissues' dielectric properties. A significant contrast between electric field values of the normal and stroke-affected brain tissues was observed at the stroke location. This is a step towards generating MW scattering information for the development of an efficient image reconstruction algorithm.