Rice Consumption and Subclinical Lung Disease in US Adults: Observational Evidence From the Multi-Ethnic Study of Atherosclerosis.
Rice accumulates arsenic, an established lung toxicant. Little is known about the association of rice consumption with arsenic-related health effects, particularly interstitial lung disease. Between 2000 and 2002, 6,814 white, black, Hispanic, and Chinese adults from 6 US cities were enrolled in the Multi-Ethnic Study of Atherosclerosis. We included 2,250 participants who had spirometry data, 2,557 with full-lung computed tomography (CT) scans, and 5,710 with cardiac CT scans. Rice consumption and 310 participants with urinary arsenic were assessed at baseline. Spirometry and full-lung CT-derived measures of total lung capacity and high attenuation area (HAA), and interstitial lung abnormalities were measured at examination 5. Cardiac CT-derived HAA was measured at 1-3 visits. Twelve percent of participants reported eating at least 1 serving of rice daily. Comparing data between that group with those who ate less than 1 serving weekly, the mean difference for forced vital capacity was -102 (95% confidence interval (CI): -198, -7) mL, and for forced expiratory volume in 1 second was -90 (95% CI: -170, -11) mL after adjustment for demographics, anthropometrics, dietary factors, and smoking. The cross-sectional adjusted percent difference for total lung capacity was -1.33% (95% CI: -4.29, 1.72) and for cardiac-based HAA was 3.66% (95% CI: 1.22, 6.15). Sensitivity analyses for urinary arsenic were consistent with rice findings. Daily rice consumption was associated with reduced lung function and greater cardiac-based HAA.


Synthesis, Duplex-Forming Ability, and Enzymatic Stability of Oligonucleotides Modified with Amide-Linked Dinucleotides Containing a 3',4'-Tetrahydropyran-Bridged Nucleic Acid.
Replacement of a phosphodiester linkage with an amide linkage can improve the binding affinity of oligonucleotides to complementary RNA and their stability toward nucleases. In addition, restricting the conformation of the sugar moiety and the phosphate backbone in oligonucleotides effectively improves duplex stability. In this study, we designed amide-linked dinucleotides containing a 3',4'-tetrahydropyran-bridged nucleic acid (3',4'-tpBNA) with a constrained sugar conformation as well as a torsion angle ε. Phosphoramidites of the designed dinucleotides were synthesized and incorporated into oligonucleotides. Conformational analysis of the synthesized dinucleotides showed that the sugar conformation of the S-isomer of the amide-linked dinucleotide containing 3',4'-tpBNA was N-type, which has the same conformation as that of the RNA duplex, while that of another R-isomer was S-type. Tm analysis indicated that the oligonucleotides containing the synthesized S-isomer showed RNA-selective hybridizing ability, although their duplex-forming ability was slightly inferior to that of natural oligonucleotides. Interestingly, the stability of the oligonucleotides toward endonucleases was significantly improved by modification with the two types of amide-linked dinucleotides developed in this study.


First successful treatment of a circumferential intramural esophageal dissection with perforation in a patient with eosinophilic esophagitis using a partially covered self-expandable metal stent.
Intramural esophageal dissection (IED) is a rare disease characterized by a partial (PIED) or circumferential (CIED) mucosal rupture. Whereas PIED responds well to nonoperative treatment, complicated courses have been reported necessitating surgery, up to the point of esophagectomy despite complex endoscopic interventions, in CIED. We report the first case of an iatrogenic CIED with perforation in a young patient with underlying eosinophilic esophagitis treated successfully by endoscopy alone, using a partially covered self-expandable metal stent.


Misperceptions, misinformation and myths about modern contraceptive use in Ghana.
Ghana, like the rest of West Africa, has very low contraceptive prevalence and is one of a few nations that reports declines in contraceptive use over time based on two of the most recent national surveys. Fear of side effects is a leading cause of non-use of contraception, based on national surveys. The objective of this study was to gain a more holistic understanding of why Ghanaian women are not using contraception. We used focus groups with vignettes to elicit normative beliefs about contraception. We recruited 91 women from three different clinics within Legon Hospital in Accra, Ghana: the antenatal clinic, the student clinic and the child welfare clinic. Focus groups were homogeneous with regard to age group and union status. We found that women were most concerned with the menstrual irregularities caused by hormonal methods. In addition, women believed strongly that the hospital was the best place to get contraception as blood tests were needed to match women with the appropriate method. Knowledge of how methods worked and of basic reproductive biology was low. Poor knowledge of how to use modern methods combined with myths and misinformation should be the targets of programmes to increase modern contraceptive prevalence in Ghana.


Are subjects satisfied with the informed consent process? A survey of research participants.
Letters of information (LOI) for clinical trials are becoming longer and more complicated. We investigated patients' perspectives of their ability to understand the information presented during a clinical trial. Satisfaction with and motivation for participation in clinical trials were also ascertained. Perceptions from various treatment disciplines were compared. Participants were chosen from 14 clinical trials (departments of rheumatology, ophthalmology, and cardiology) conducted at the same university. Subjects were asked to complete a written questionnaire that assessed demographic information, recall and understanding of information, subjects' decisions to participate, and perceptions/opinions of the study. The response rate was 75% (rheumatology, n = 74; ophthalmology, n = 32; cardiology, n = 84). The majority of respondents (98%) indicated that they were satisfied with the informed consent process and with their involvement in a trial (97%). Subjects who reported having understood the LOI had better recall of placebo/active drug comparator (p < 0.03), and better understanding of why placebo was used (p < 0.04). No differences were found between those who reported understanding and those who did not on understanding the concept of concealed allocation (blinding). Subjects who felt they had received "the right amount of information" were more likely not to understand concealed allocation. The most frequent reason for trial participation was to help medical science (80%). Subjects with higher education were more likely to understand the reason for placebo use (p < 0.0003), but were not more likely to understand concealed allocation (p < 0.08). Subjects reported that they were satisfied with the informed consent process and their experience in a clinical trial, and that they understood trial concepts. Subjects may be able to self-assess their own level of understanding for trial concepts that intrinsically make sense within the context of their beliefs about medical care, but other trial concepts may be misunderstood/misinterpreted regardless of self-assessment of understanding or education level (i.e., concealed allocation). Subjects may prefer to believe that investigators know which treatment they are receiving, and have made a good treatment decision specific to their case, despite having being told about concealed allocation and placebo use.


Ingestion of a cold temperature/menthol beverage increases outdoor exercise performance in a hot, humid environment.
A recent laboratory study demonstrated that the ingestion of a cold/menthol beverage improved exercise performance in a hot and humid environment during 20 km of all-out cycling. Therefore, the aim of this study was to determine whether the ingestion of cold water/ice-slurry with menthol would improve performance in hot and humid outdoor conditions. Ten trained males completed three trials of five blocks consisting of 4-km cycling and 1.5-km running. During warm-up, every block and recovery, the athletes drank 190 ml of aromatized (i.e., with 0.05 mL of menthol) beverage at three temperatures: Neutral (ambient temperature) (28.7°C±0. 5°C), Cold (3.1°C±0.6°C) or Ice-slurry (0.17°C±0.07°C). Trial time, core temperature (Tco), heart rate (HR), rate of perceived exertion (RPE), thermal sensation (TS) and thermal comfort (TC) were assessed. Ice-slurry/menthol increased performance by 6.2% and 3.3% compared with neutral water/menthol and cold water/menthol, respectively. No between-trial differences were noted for Tco, HR, RPE, TC and TS was lower with ice-slurry/menthol and cold water/menthol compared with neutral water/menthol. A low drink temperature combined with menthol lessens the performance decline in hot/humid outdoor conditions (i.e., compared with cold water alone). Performances were better with no difference in psycho-physiological stress (Tco, HR and RPE) between trials. The changes in perceptual parameters caused by absorbing a cold/menthol beverage reflect the psychological impact. The mechanism leading to these results seems to involve brain integration of signals from physiological and psychological sources.


[Microbiological quality of hemodialysis water: what are the risk factors?]
A dialyzed patient weekly gets in touch with a large amount of water (on average 350 liters) through the dialysis bath. It is therefore essential that this solution would have a high quality and purity. The aim of our study was to monitor the microbiological quality of the hemodialysis water in order to identify possible factors that could affect it. We conducted a cross-sectional study from January 2015 to October 2017 collecting the dialysis water in AOU Careggi. Samples were aseptically collected by specialized technicians and then transported under ice at 4° C to the Laboratory of Biological Hazards of USL Toscana Centro for laboratory analyses. 126 water samples were collected. Coliforms, E. coli, Staphylococcus aureus, enterococci were not detected. Pseudomonas aeruginosa was found in only one sample. Both for CFU at 37° C and at 22° C, the type of device represented the only statistically significant risk factor (OR 15.21 and OR 10.25 respectively): SDS devices had a significantly higher risk of being positive for CFU at 37° C and 22° C. As our study demonstrated, the system producing dialysis water must be constantly monitored, especially in cases of SDS devices which may be subjected more frequently to a higher contamination, due to their discontinuous use.


Test-enhanced learning in the classroom: long-term improvements from quizzing.
Three experiments examined whether quizzing promotes learning and retention of material from a social studies course with sixth grade students from a suburban middle school. The material used in the experiments was the course material students were to learn and some of the dependent measures were the actual tests on which students received grades. In within-subject designs, students received three low-stakes multiple-choice quizzes in Experiments 1 and 2 and performance on quizzed items was compared to that on items that were presented twice (Experiment 2) or items that were not presented on the initial quizzes (Experiments 1 and 2). We found that students' performance on both chapter exams and semester exams improved following quizzing relative to either not being quizzed or relative to the twice-presented items. In Experiment 3, students were given one multiple-choice quiz in class and encouraged to quiz themselves outside of class using a Web-based system. The assessment in this experiment was a short answer test in which students had to produce answers, but we also used multiple-choice tests. Once again, we found that quizzing of material produced a positive effect on chapter and semester exams. These results show the robustness of retrieval practice via testing as a learning mechanism in a classroom setting using the subject matter of the course and (in most cases) the tests on which students received grades as the dependent measures. Our results add to a growing body of evidence that retrieval practice in the classroom can boost academic performance.


Substance P-containing projections in the dorsal columns of rats and cats.
Light and electron microscopic immunocytochemical methods were used to study the distribution and the morphology of substance P-positive fibers and axon terminals in the dorsal column nuclei of rats and cats, and to determine whether they are part of an ascending input to these nuclei. In rats, substance P-positive fibers and axon terminals are present throughout the rostrocaudal extent of the dorsal column nuclei. In cats, immunostained fibers and terminals are mostly confined to the ventral region of the caudal and middle portions of these nuclei but they are more homogeneously distributed at rostral levels. In both species, substance P-positive neurons are not present in the same nuclear complex. At the electron microscope level, substance P-positive terminals are small- to medium-sized and dome-shaped; they form asymmetric contacts on dendrites and contain many round, agranular vesicles and sparse dense core vesicles. In double-labeling experiments, visualization of substance P-immunoreactivity in the dorsal root ganglia and dorsal horn of the spinal cord was combined with the retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase or of colloidal gold-labeled wheat germ agglutinin conjugated to enzymatically inactive horseradish peroxidase. These experiments show that substance P-positive axon terminals may originate from both small dorsal root ganglion neurons and from spinodorsal column nuclei neurons in lamina IV. Although quantitative evaluation of the contribution of these two pathways to the substance P innervation of the dorsal column nuclei has not been performed and other sources cannot be discarded on the basis of the present evidence, it is proposed that non-primary afferents to the dorsal column nuclei account for most of the substance P-positive fibers and terminals in the dorsal column nuclei. The experiments support previous findings suggesting that nociceptive input may access the dorsal column nuclei and that this may be mediated, though to a very limited extent, directly by way of small dorsal root ganglion neurons.


Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival.
Human mesenchymal stem cells (hMSCs) have been shown to reside as stromal cells in human gliomas as glioma-associated hMSCs (GA-hMSCs), but their biological role remains unclear. Because recent evidence indicates that GA-hMSCs drive tumor cell proliferation and stemness, we hypothesized that a higher percentage of GA-hMSCs in tumors predicts poor patient prognosis. We determined the percentage of cells coexpressing GA-hMSC markers CD105+/CD73+/CD90+ from patients with newly diagnosed high-grade glioma and analyzed the association between this percentage and overall survival (OS) in 3 independent cohorts: fresh surgical glioblastoma specimens (cohort 1, N = 9), cultured tumor specimens at passage 3 (cohort 2, N = 28), and The Cancer Genome Atlas (TCGA) database. In all cohorts, patient OS correlated with the percentages of GA-hMSCs in tumors. For cohort 1, the median OS of patients with tumors with a low percentage of triple-positive cells was 46 months, and for tumors with a high percentage of triple-positive cells, it was 12 months (hazard ratio [HR] = 0.24; 95% CI: 0.02-0.5, P = .02). For cohort 2, the median OS of patients with tumors with a low percentage of GA-hMSCs was 66 months, and for tumors with a high percentage, it was 11 months (HR = 0.38; 95% CI: 0.13-0.9, P = .04). In the database of TCGA, the median OS times in patients with high and low coexpression levels of CD105/CD73/CD90 were 8.4 months and 13.1 months (HR = 0.4; 95% CI: 0.1-0.88; P = .04), respectively. The percentage of GA-MSCs inversely correlates with OS, suggesting a role for GA-MSCs in promoting aggressive behavior of gliomas.


Mouse BAZ1A (ACF1) is dispensable for double-strand break repair but is essential for averting improper gene expression during spermatogenesis.
ATP-dependent chromatin remodelers control DNA access for transcription, recombination, and other processes. Acf1 (also known as BAZ1A in mammals) is a defining subunit of the conserved ISWI-family chromatin remodelers ACF and CHRAC, first purified over 15 years ago from Drosophila melanogaster embryos. Much is known about biochemical properties of ACF and CHRAC, which move nucleosomes in vitro and in vivo to establish ordered chromatin arrays. Genetic studies in yeast, flies and cultured human cells clearly implicate these complexes in transcriptional repression via control of chromatin structures. RNAi experiments in transformed mammalian cells in culture also implicate ACF and CHRAC in DNA damage checkpoints and double-strand break repair. However, their essential in vivo roles in mammals are unknown. Here, we show that Baz1a-knockout mice are viable and able to repair developmentally programmed DNA double-strand breaks in the immune system and germ line, I-SceI endonuclease-induced breaks in primary fibroblasts via homologous recombination, and DNA damage from mitomycin C exposure in vivo. However, Baz1a deficiency causes male-specific sterility in accord with its high expression in male germ cells, where it displays dynamic, stage-specific patterns of chromosomal localization. Sterility is caused by pronounced defects in sperm development, most likely a consequence of massively perturbed gene expression in spermatocytes and round spermatids in the absence of BAZ1A: the normal spermiogenic transcription program is largely intact but more than 900 other genes are mis-regulated, primarily reflecting inappropriate up-regulation. We propose that large-scale changes in chromatin composition that occur during spermatogenesis create a window of vulnerability to promiscuous transcription changes, with an essential function of ACF and/or CHRAC chromatin remodeling activities being to safeguard against these alterations.


Optimal number of response categories in rating scales: reliability, validity, discriminating power, and respondent preferences.
Using a self-administered questionnaire, 149 respondents rated service elements associated with a recently visited store or restaurant on scales that differed only in the number of response categories (ranging from 2 to 11) and on a 101-point scale presented in a different format. On several indices of reliability, validity, and discriminating power, the two-point, three-point, and four-point scales performed relatively poorly, and indices were significantly higher for scales with more response categories, up to about 7. Internal consistency did not differ significantly between scales, but test-retest reliability tended to decrease for scales with more than 10 response categories. Respondent preferences were highest for the 10-point scale, closely followed by the seven-point and nine-point scales. Implications for research and practice are discussed.


Deintensification of Adjuvant Treatment After Transoral Surgery in Patients With Human Papillomavirus-Positive Oropharyngeal Cancer: The Conception of the PATHOS Study and Its Development.
PATHOS is a phase II/III randomized controlled trial (RCT) of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery (TOS) for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). The study opened in the UK in October 2015 and, after successful recruitment into the phase II, transitioned into phase III in the autumn of 2018. PATHOS aims to establish whether the de-intensification of adjuvant treatment in patients with favorable prognosis HPV-positive OPSCC will confer improved swallowing outcomes, whilst maintaining high rates of cure. In this article, we will outline the rationale for the study and how it aims to answer fundamentally important questions about the safety, effectiveness and functional outcomes of minimally invasive TOS techniques followed by adjuvant radiotherapy (RT) or chemo-radiotherapy (CRT) in this patient population.


Practical Difficulties in Estimating The Prevalence of Primary Infertility in Iran.
According to the World Health Organization (WHO)'s clinical, epidemiological and demographic definitions, infertility is an inability to become pregnant within one, two or five years of exposure to pregnancy, respectively. Inconsistent infertility-related definitions and various methodological approaches make it difficult to compare quantitative data in this regard and consequently, have negatively influenced estimating the prevalence of infertility. The present study reviewed the results of a large population-based survey on how the clinical, epidemiological and demographic definitions of infertility produce different results in terms of infertility prevalence in Iran and subsequently, compared the findings in order to find the right time of treatment-seeking by couples. This community-based, cross-sectional study was carried out by Avicenna Research Institute in the urban and rural parts of Iran between 2010 and 2011. Using cluster sampling, the reproductive history of 17,187 married women aged 20-40 years, was recorded. Totally, 1011 clusters were randomly selected according to post office codes, proportional to the population of the province. Descriptive and inferential statistical analysis of the data was carried out by SPSS statistical software. The prevalence of primary infertility based on the WHO's clinical, epidemiological and demographic definitions were 20.2, 12.8 and 9.2%, respectively. In addition, secondary infertility rate was 4.9%. Infertility estimates over a two-year exposure period made a 50% decrease in infertility rate; however, increasing exposure period to five years made no significant difference in infertility rate. The findings showed that most of the couples will get pregnant within two years of unprotected sexual intercourse and thus, need no treatment. Due to practical difficulties in estimating the prevalence of primary infertility, the reference limit for time to pregnancy, should be reconsidered and giving more time to younger women to become pregnant, seems reasonable.


Impacts of the 2014 severe drought on the Microcystis bloom in San Francisco Estuary.
The increased frequency and intensity of drought with climate change may cause an increase in the magnitude and toxicity of freshwater cyanobacteria harmful algal blooms (CHABs), including Microcystis blooms, in San Francisco Estuary, California. As the fourth driest year on record in San Francisco Estuary, the 2014 drought provided an opportunity to directly test the impact of severe drought on cyanobacteria blooms in SFE. A field sampling program was conducted between July and December 2014 to sample a suite of physical, chemical, and biological variables at 10 stations in the freshwater and brackish reaches of the estuary. The 2014 Microcystis bloom had the highest biomass and toxin concentration, earliest initiation, and the longest duration, since the blooms began in 1999. Median chlorophyll a concentration increased by 9 and 12 times over previous dry and wet years, respectively. Total microcystin concentration also exceeded that in previous dry and wet years by a factor of 11 and 65, respectively. Cell abundance determined by quantitative PCR indicated the bloom contained multiple potentially toxic cyanobacteria species, toxic Microcystis and relatively high total cyanobacteria abundance. The bloom was associated with extreme nutrient concentrations, including a 20-year high in soluble reactive phosphorus concentration and low to below detection levels of ammonium. Stable isotope analysis suggested the bloom varied with both inorganic and organic nutrient concentration, and used ammonium as the primary nitrogen source. Water temperature was a primary controlling factor for the bloom and was positively correlated with the increase in both total and toxic Microcystis abundance. In addition, the early initiation and persistence of warm water temperature coincided with the increased intensity and duration of the Microcystis bloom from the usual 3 to 4 months to 8 months. Long residence time was also a primary factor controlling the magnitude and persistence of the bloom, and was created by a 66% to 85% reduction in both the water inflow and diversion of water for agriculture during the summer. We concluded that severe drought conditions can lead to a significant increase in the abundance of Microcystis and other cyanobacteria, as well as their associated toxins.


Heterotypic recognition of foot-and-mouth disease virus by cattle lymphocytes.
Lymphoproliferation against foot-and-mouth disease (FMD) virus was examined using peripheral blood mononuclear cells from vaccinated cattle. Ten weeks after revaccination the optimum conditions for proliferation were obtained with 1 microgram/ml of purified virus after 5 to 6 days in culture. This contrasted with the response at 20 months post-revaccination, when the response required less antigen and showed a peak response after 3 to 4 days in culture. Proliferation was specific for FMD virus, but was cross-reactive between serotypically distinct strains of the virus. The proliferative response to isolated virus proteins (VP) involved all three major capsid proteins (VP1, -2 and -3), although the proliferation of lymphocytes from heterotypically vaccinated cattle was due to VP3. Furthermore, the response induced by purified virus, chemically fixed virus and subunit virus particles was indistinguishable and thus it is likely that processing was required for the induction of proliferation. Together these data strongly suggest that FMD virus-induced lymphoproliferation is T cell-mediated and that VP3 may contain dominant, cross-reactive sequences.


Classification of underground pipe scanned images using feature extraction and neuro-fuzzy algorithm.
Pipeline surface defects such as holes and cracks cause major problems for utility managers, particularly when the pipeline is buried under the ground. Manual inspection for surface defects in the pipeline has a number of drawbacks, including subjectivity, varying standards, and high costs. Automatic inspection system using image processing and artificial intelligence techniques can overcome many of these disadvantages and offer utility managers an opportunity to significantly improve quality and reduce costs. A recognition and classification of pipe cracks using images analysis and neuro-fuzzy algorithm is proposed. In the preprocessing step the scanned images of pipe are analyzed and crack features are extracted. In the classification step the neuro-fuzzy algorithm is developed that employs a fuzzy membership function and error backpropagation algorithm. The idea behind the proposed approach is that the fuzzy membership function will absorb variation of feature values and the backpropagation network, with its learning ability, will show good classification efficiency.


Application of the tris(acetylacetonato)iron(III)/(II) redox couple in p-type dye-sensitized solar cells.
An electrolyte based on the tris(acetylacetonato)iron(III)/(II) redox couple ([Fe(acac)3](0/1-)) was developed for p-type dye-sensitized solar cells (DSSCs). Introduction of a NiO blocking layer on the working electrode and the use of chenodeoxycholic acid in the electrolyte enhanced device performance by improving the photocurrent. Devices containing [Fe(acac)3](0/1-) and a perylene-thiophene-triphenylamine sensitizer (PMI-6T-TPA) have the highest reported short-circuit current (J(SC)=7.65 mA cm(-2)), and energy conversion efficiency (2.51%) for p-type DSSCs coupled with a fill factor of 0.51 and an open-circuit voltage V(OC)=645 mV. Measurement of the kinetics of dye regeneration by the redox mediator revealed that the process is diffusion limited as the dye-regeneration rate constant (1.7×10(8) M(-1) s(-1)) is very close to the maximum theoretical rate constant of 3.3×10(8) M(-1) s(-1). Consequently, a very high dye-regeneration yield (>99%) could be calculated for these devices.


The slack sodium-activated potassium channel provides a major outward current in olfactory neurons of Kv1.3-/- super-smeller mice.
The Kv1.3 voltage-dependent potassium channel is expressed at high levels in mitral cells of the olfactory bulb (OB). Deletion of the Kv1.3 potassium channel gene (Kv1.3-/-) in mice lowers the threshold for detection of odors, increases the ability to discriminate between odors, and alters the firing pattern of mitral cells. We have now found that loss of Kv1.3 produces a compensatory increase in Na(+)-activated K(+) currents (K(Na)) in mitral cells. Levels of the K(Na) channel subunit Slack-B determined by Western blotting are substantially increased in the OB from Kv1.3-/- animals compared with those of wildtype animals. In voltage-clamp recordings of OB slices, elevation of intracellular sodium from 0 to 60 mM increased mean outward currents by 15% in mitral cells from wildtype animals and by 40% in cells from Kv1.3-/- animals. In Kv1.3-/- cells, K(Na) current could even be detected with 0 mM Na(+) internal solutions, provided extracellular Na(+) was present, and this current could be abolished by TTX and ZD7288, blockers of Na(+) influx through voltage-dependent Na(+) channels and H-channels, respectively. The role of enhanced expression of Slack subunits in the increase of K(Na) current in Kv1.3-/- cells was also confirmed using an RNA interference (RNA(i)) approach to suppress Slack expression in primary cultures of olfactory neurons. In Kv1.3-/- neurons, treatment with Slack-specific RNA(i) inhibited approximately 75% of the net outward current, whereas in wildtype cells, the same treatment suppressed only about 25% of the total current. Scrambled and mismatched RNA(i) oligonucleotides failed to suppress currents. Our findings raise the possibility that the olfactory phenotype of Kv1.3-/- animals results in part from an enhancement of K(Na) currents.


The incidence of stroke after myocardial infarction: a meta-analysis.
While the risk of stroke after myocardial infarction (MI) is increased compared with the risk among those without MI, the magnitude of this risk remains unclear. Although numerous clinical trials have reported the incidence of stroke following MI, these are among selected populations. We reviewed cohort studies reporting the incidence of stroke after MI to better define the risk of ischemic stroke in an unselected population. A computerized literature search (MEDLINE and PubMed) and manual review of reference lists of identified articles were conducted. Population-based studies published from 1978-2004 with at least 100 subjects that reported number or percent of ischemic strokes experienced by MI survivors were identified. Data were extracted using standardized forms, and study quality was assessed by 2 independent reviewers. Ischemic stroke rates were reported as number of events per 1000 MI with 95% confidence intervals (CI) calculated by Poisson distribution. A combined stroke rate was calculated for in-hospital, 30 days, and 1-year post-MI using weights of 1/variance. A random-effects model also was created to estimate in-hospital stroke rate. Variability in study designs and outcome definitions limit synthesis of available data. During hospitalization for the index MI, 11.1 ischemic strokes occurred per 1000 MI compared with 12.2 at 30 days and 21.4 at 1 year. Using a random-effects model, 14.5 strokes occurred per 1000 MI. Positive predictors of stroke after MI included: advanced age, diabetes, hypertension, history of prior stroke, anterior location of index MI, prior MI, atrial fibrillation, heart failure, and nonwhite race. The public health implications of stroke among MI survivors, as well as the large number of MI survivors, underscore the need to be aware of this devastating complication. Further research is needed to determine the optimal stroke prevention strategies for MI survivors.


Clinical therapeutic effect and biological monitoring of p53 gene in advanced hepatocellular carcinoma.
To investigate the therapeutic effect and biological changes of hepatic arterial infusion of p53 gene by the percutaneous port catheter system on advanced hepatocellular carcinoma (HCC) through a prospective randomized trial. A total of 48 patients with advanced HCC between May 2005 and January 2009 were divided into the treatment group (30) and the control group (18). The port catheter system was implanted through the right external iliac artery approach in all the cases; the target artery was determined according to the manifestation of the angiograph. The patients in the treatment group were given arterial infusion of p53 gene (Gendicine, Shenzhen Sibiono GeneTech Co, Ltd) with Gendicine (10vp) combined with hydroxycamptothecin (20 mg), once a week, for a course continuously for 3 weeks. The arterial infusion with hydroxycamptothecin (20 mg) was given to the patients in the control group. Pretreatment/posttreatment a fetus protein and Karnofsky Performance Status values, change of tumor according to Response Evaluation Criteria in Solid Tumors (RECIST), and the survival time were analyzed. Pretreatment/posttreatment expression of mutant p53 gene and spontaneous micronucleus formation in the peripheral blood were evaluated by flow cytometry and micronucleus test in vivo. The patients in the treatment group received 1 to 8 courses of treatment, in which the differences between pretreatment/posttreatment AFP and KPS values were significant (P < 0.05), whereas there was no significant difference (P > 0.05) between pretreatment/posttreatment AFP and KPS values within the control group. After 1 month, the survival rates of the treatment and control groups (96.6% and 94.4%, respectively) and changes in the tumor evaluated according to RECIST were significantly different (P < 0.05) between the 2 groups. After 3 months, the survival rates of the treatment and control groups (83.3% and 55.6%, respectively) and changes in the tumor were also significantly different between the 2 groups (P < 0.05). After 6 months, the survival rates (50% and 11%, respectively) and changes in the tumor were significantly different between the 2 groups (P < 0.05). After 9 months, the survival rates (23.3% and 0%, respectively) and changes in the tumor were significantly different between the 2 groups (P < 0.05). Finally, after 12 months, the survival rates (6.67% and 0%, respectively) and changes in the tumor were significantly different between the 2 groups (P < 0.05). The difference between the pretreatment and posttreatment mean rates of p53 expression in patients in the treatment group was very significant (P < 0.01). The difference between the posttreatment mean rates of the treatment group and the control group was also significant. Sequential therapy of p53 gene transcatheter arterial infusion was safe and could prolong the survival time of the patients. The biological study will play a positive role in guiding and monitoring the aspects of dosage selection and judgment of therapeutic efficacy.


Explicit formulation of different receptor-G-protein interactions and effector regulation.
G-protein-coupled receptors (GPCRs) can create different intracellular signals depending on which G-proteins they couple to and which intracellular signal-integrators, such as adenylyl cyclases, are expressed in the cell. One and the same GPCR can activate multiple G-protein species, generating signals, which either inhibit or amplify each other. Because of this complexity, extraction of mechanistic information from concentration-response curves is not straightforward. To tackle this problem, I describe in this paper explicit equations for GPCR-interaction with two G-protein species by different possible mechanisms, and also an equation for the regulation of an effector enzyme by the activated G-proteins or their effectors. Arithmetic solutions to these equations are presented, which resulted in the equations being applicable in a spreadsheet program environment. These equations are useful in simulations to analyze results, to design experiments and to test hypotheses. Some examples of this are presented in this study.


Laser-induced fluorescence detection of hydroxyl (OH) radical by femtosecond excitation.
The development of a laser-induced fluorescence detection scheme for probing combustion-relevant species using a high-repetition-rate ultrafast laser is described. A femtosecond laser system with a 1 kHz repetition rate is used to induce fluorescence, following two-photon excitation (TPE), from hydroxyl (OH) radicals that are present in premixed laminar flames. The experimental TPE and one-photon fluorescence spectra resulting from broadband excitation into the (0,0) band of the OH A(2)∑(+)-X(2)Π system are compared to simulated spectra. Additionally, the effects of non-transform-limited femtosecond pulses on TPE efficiency is investigated.


[Familial spastic spinal paralysis--clinical spectrum and differential diagnostic considerations].
The familial spastic paraplegia is a rare disorder of the cerebral nervous system characterized by a slowly progressive spasticity of the lower limbs with early or late onset. There are pure and complicated forms. The disease is inherited by an autosomal dominant mode and a recessive one. In this study 6 patients out of 5 families are presented. The clinical variety, genetic aspects, electrophysiological results and differential diagnosis are discussed.


Adjusting adjustable eye muscle sutures in anesthetized patients.
This study evaluated the predictability of results by adjusting eye muscle sutures in anesthetized patients. Consideration was given to the differences in the eye positions when the patient was awake and anesthetized. Observations were made under what the anesthesiologist considered was plane two of surgical anesthesia with the eyes in a stable position. Care was taken that effects of depolarizing agents, if given, had worn off. Twenty-nine operations were performed on 28 patients. Results at six months after surgery were consistent within 5 degrees (10 PD) of orthotropia in 25 operations. There were three cases of undercorrected vision by 6 degrees in patients with esotropia. These patients required no additional surgery. One patient had a 10 degrees difference from the anticipated result.


MRI, CT, and PET/CT for ovarian cancer detection and adnexal lesion characterization.
The purpose of this article is to describe the role of MR, CT, and PET/CT in the detection of ovarian cancer and the evaluation of adnexal lesions. The goal of imaging in ovarian cancer detection is to expeditiously distinguish benign adnexal lesions from those requiring further pathologic evaluation for malignancy. For lesions indeterminate on ultrasound, MRI increases the specificity of imaging evaluation, thus decreasing benign resections. CT is useful in diagnosis and treatment planning of advanced cancer. Although (18)F-FDG-avid ovarian lesions in postmenopausal women are considered suspicious for malignancy, PET/CT is not recommended for primary cancer detection because of high false-positive rates.


Potential predictive factors for successful referral from specialist mental-health services to less intensive treatment: A concept mapping study.
Referring patients from specialist mental-health services (provided by multiple healthcare service providers and aimed at relieving symptoms of mental illness) to less intensive care (provided by a nurse or psychologist in cooperation with a general practitioner and aimed at improving quality of life) is feasible from the perspective of patients, service providers, and mental-health services. However, it is unclear which patients are most suitable for referral to less intensive care. In this study, we used concept mapping to identify factors that might determine whether a referral from specialist mental services to less intensive care might be successful. Participants (N = 34) were recruited from different parts of the Netherlands and included general practitioners, peer workers, community mental-health nurses, and social workers from several services who were based in different neighborhoods. The participants generated 54 statements (31 after clean-up), which were sorted into five clusters and rated on their expected ability to predict successful referral. Ordered from highest to lowest on expected predictive value, the clusters of factors were: Patient characteristics, patients' informal support system, patients' social situation, organization of services, and service provider related factors. The ordering was the same for all of the service providers, except that general practitioners expected the organization of services to be the most predictive. The ordering of the clusters is mostly consistent with existing knowledge about recovery during mental healthcare. In order to further improve the number of successful referrals from specialist mental-health services to less intensive care, a prospective prediction study is needed.


Vesicular Glutamate Transporter 1 Knockdown in Infralimbic Prefrontal Cortex Augments Neuroendocrine Responses to Chronic Stress in Male Rats.
Chronic stress-associated pathologies frequently associate with alterations in the structure and activity of the medial prefrontal cortex (mPFC). However, the influence of infralimbic cortex (IL) projection neurons on hypothalamic-pituitary-adrenal (HPA) axis activity is unknown, as is the involvement of these cells in chronic stress-induced endocrine alterations. In the current study, a lentiviral-packaged vector coding for a small interfering RNA (siRNA) targeting vesicular glutamate transporter (vGluT) 1 messenger RNA (mRNA) was microinjected into the IL of male rats. vGluT1 is responsible for presynaptic vesicular glutamate packaging in cortical neurons, and knockdown reduces the amount of glutamate available for synaptic release. After injection, rats were either exposed to chronic variable stress (CVS) or remained in the home cage as unstressed controls. Fifteen days after the initiation of CVS, all animals were exposed to a novel acute stressor (30-minute restraint) with blood collection for the analysis of adrenocorticotropic hormone (ACTH) and corticosterone. Additionally, brains were collected for in situ hybridization of corticotrophin-releasing hormone mRNA. In previously unstressed rats, vGluT1 siRNA significantly enhanced ACTH and corticosterone secretion. Compared with CVS animals receiving the green fluorescent protein control vector, the vGluT1 siRNA further increased basal and stress-induced corticosterone release. Further analysis revealed enhanced adrenal responsiveness in CVS rats treated with vGluT1 siRNA. Collectively, our results suggest that IL glutamate output inhibits HPA responses to acute stress and restrains corticosterone secretion during chronic stress, possibly at the level of the adrenal. Together, these findings pinpoint a neurochemical mechanism linking mPFC dysfunction with aberrant neuroendocrine responses to chronic stress.


Impaired retinal circulation in patients with type 2 diabetes mellitus: retinal laser Doppler velocimetry study.
To evaluate the differences in retinal circulation in eyes of patients with type 2 diabetes with no or early-stage diabetic retinopathy compared with control eyes. Seventy-five nondiabetic eyes and 194 eyes with type 2 diabetes mellitus were evaluated. The type 2 diabetic eyes were classified into two groups: 139 eyes (139 patients) without diabetic retinopathy (NDR) and 55 eyes (55 patients) with mild nonproliferative diabetic retinopathy (NPDR). The retinal circulatory parameters were measured with laser Doppler velocimetry, and the factors that affect retinal hemodynamics were determined in a cross-sectional population of patients with type 2 diabetes. The group-averaged blood velocity (V) and retinal blood flow (RBF) in the NDR and mild NPDR groups were significantly (P < 0.01) lower than in the non-DM group. The diameter and wall shear rate were also significantly (P < 0.05) lower in the NDR group than in the nondiabetic control eyes. Multiple regression analysis showed that the RBF was independently and negatively correlated with serum low-density lipoprotein and creatinine. HbA1c was significantly (P < 0.05) higher in participants in the lowest RBF quartile than in the highest quartiles. The results indicate that the RBF may decrease in patients with type 2 diabetes without retinopathy and in those with mild retinopathy.


Cytotoxicity of alkaloids isolated from Peganum harmala seeds.
Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seed-extract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction (TAF) in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine (vasicine) and vasicinone were isolated from the P. harmala seed-extract and their activity and that of TAF were tested a) for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1) Med-mek carcinoma ; 2) UCP-med carcinoma ; 3) UCP-med sarcoma] ; and 4) SP2/O-Ag14, and b) for antiproliferative effect on cells of Jurkat, E6-1 clone (inhibition of incorporation of {(3)H-thymidine} in cellular DNA). The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC50 values (concentration of the active substance that inhibited the growth of the tumor cells by 50%) ranging between 2.43 μg/mL and 19.20 μg/mL, while UCP-med carcinoma was the least sensitive (range of IC50 = 13.83 μg/mL to 59.97 μg/mL). Of the substances evaluated, harmine was the most active compound (IC50 for the 4 tumor cell lines varying between 2.43 μg/mL and 18.39 μg/mL), followed by TAF (range of IC50 = 7.32 μg/mL to 13.83 μg/mL); peganine was the least active (IC50 = 50 μg/mL to > 100 μg/mL). In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of {(3)H-TDR} in the DNA cells of Jurkat, E6-1 clone by 50% (IC50) were 8.60 ± 0.023 μg/mL and 8.94 ± 0.017 μg/mL, respectively, while peganine was the least active (IC50 >100 μg/mL). The IC50 values for harmalacidine (27.10 ± 0.011 μg/mL) and harmine (46.57 ± 0.011 μg/mL) were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity.


The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis.
Telomeres are essential for chromosomal integrity and stability. Shortened telomere length (TL) has been associated with risk of cancers and aging-related diseases. Several studies have explored associations between TL and cancer prognosis, but the results are conflicting. Prospective studies on the relationship between TL and cancer survival were identified by a search of PubMed up to May 25, 2015. There were no restrictions on the cancer type or DNA source. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Meta-analysis approaches were conducted to determine pooled relative risks and 95% confidence intervals. Thirty-three articles containing forty-five independent studies were ultimately involved in our meta-analysis, of which twenty-seven were about overall cancer survival and eighteen were about cancer progression. Short TL was associated with increased cancer mortality risk (RR = 1.30, 95%CI: 1.06-1.59) and poor cancer progression (RR = 1.44, 95%CI: 1.10-1.88), both with high levels of heterogeneity (I2 = 83.5%, P = 0.012for overall survival and I2 = 75.4%, P = 0.008 for progression). TL was an independent predictor of overall cancer survival and progression in chronic lymphocytic leukemia. Besides, short telomeres were also associated with increased colorectal cancer mortality and decreased overall survival of esophageal cancer, but not in other cancers. Cancer progression was associated with TL in Asian and America populations and short TL predicted poor cancer survival in older populations. Compared with tumor tissue cells, TL in blood lymphocyte cells was better for prediction. In addition, the associations remained significant when restricted to studies with adjustments for age, with larger sample sizes, measuring TL using southern blotting or estimating risk effects by hazard ratios. Short TL demonstrated a significant association with poor cancer survival, suggesting the potential prognostic significance of TL. Additional large well-designed studies are needed to confirm our findings.


Lifestyle changes and glycemic control in type 1 diabetes mellitus: a trial protocol with factorial design approach.
Type 1 diabetes (T1D) has been increasing globally over the past three decades. Self-monitoring of blood glucose is a challenge in both developed as well as developing countries. Self-management guidelines include maintaining logbooks for blood glucose, physical activity, and dietary intake that affect glycated hemoglobin (HbA1c) and a multitude of life-threatening acute complications. Innovative, cost-effective interventions along with beneficial lifestyle modifications can improve home-based self-monitoring of blood glucose in T1D patients. The overall objective of this study is to evaluate the relationship between maintaining log books for blood glucose levels, reinforcement by e-messages, and/or daily step count and changes in HbA1c. A randomized controlled trial will enroll participants aged 15 years and above in four groups. Each group of 30 participants will be working with a newly designed standard log book for documenting their blood glucose. The first group will be entirely on routine clinical care, the second group will be on routine care and will receive an additional e-device for recording step count (fit bit), the third group will receive routine care and daily motivational e-messages to maintain the log book, and the fourth group along with routine care will receive an e-device for measuring step count (fit bit) and e-messages about maintaining the log book. Patients will be enrolled from pediatric and endocrine clinics of a tertiary care hospital in Karachi. All groups will be followed up for a period of 6 months to evaluate outcomes. Log book data will be obtained every 3 months electronically or during a patient's clinic visit. HbA1c as a main outcome will be measured at baseline and will be evaluated twice every 3 months. A baseline questionnaire will determine the socio-demographic, nutritional, and physical activity profile of patients. Clinical information for T1D and other co-morbidities for age of onset, duration, complications, hospitalizations, habits for managing T1D, and other lifestyle characteristics will be ascertained. Behavioral modifications for maintaining daily log books as a routine, following e-messages alone, fit bit alone, or e-messages plus using fit bit will be assessed for changes in HbA1c using a generalized estimated equation. The proposed interventions will help identify whether maintaining log books for blood glucose, motivational e-messages, and/or daily step count will reduce HbA1c levels. ClinicalTrials.gov, NCT03864991. March 6, 2019.


New whole-body sensory-motor gradients revealed using phase-locked analysis and verified using multivoxel pattern analysis and functional connectivity.
Topographic organization is one of the main principles of organization in the human brain. Specifically, whole-brain topographic mapping using spectral analysis is responsible for one of the greatest advances in vision research. Thus, it is intriguing that although topography is a key feature also in the motor system, whole-body somatosensory-motor mapping using spectral analysis has not been conducted in humans outside M1/SMA. Here, using this method, we were able to map a homunculus in the globus pallidus, a key target area for deep brain stimulation, which has not been mapped noninvasively or in healthy subjects. The analysis clarifies contradictory and partial results regarding somatotopy in the caudal-cingulate zone and rostral-cingulate zone in the medial wall and in the putamen. Most of the results were confirmed at the single-subject level and were found to be compatible with results from animal studies. Using multivoxel pattern analysis, we could predict movements of individual body parts in these homunculi, thus confirming that they contain somatotopic information. Using functional connectivity, we demonstrate interhemispheric functional somatotopic connectivity of these homunculi, such that the somatotopy in one hemisphere could have been found given the connectivity pattern of the corresponding regions of interest in the other hemisphere. When inspecting the somatotopic and nonsomatotopic connectivity patterns, a similarity index indicated that the pattern of connected and nonconnected regions of interest across different homunculi is similar for different body parts and hemispheres. The results show that topographical gradients are even more widespread than previously assumed in the somatosensory-motor system. Spectral analysis can thus potentially serve as a gold standard for defining somatosensory-motor system areas for basic research and clinical applications.


Autologous Blood Injection With Dry-Needling vs Dry-Needling Alone Treatment for Chronic Plantar Fasciitis: A Randomized Controlled Trial.
Autologous blood injection (ABI) for patients with chronic plantar fasciitis has been promoted as an approach to improve outcomes over standard dry-needling approaches. The purpose of this trial was to investigate if there are improved outcomes following an ultrasonography-guided ABI compared to dry needling alone for patients with chronic plantar fasciitis. A double-blinded (participant-blinded and observer-blinded) RCT within a single clinic enrolled 90 patients with symptoms of plantar fasciitis that had failed to improve with a minimum of 3 months of rehabilitation. The mean age was 49.5±8.9 years, 67% were female, and the mean symptom duration was 40.0±28.2 months (range: 8 months-10 years). Participants were randomized to receive ABI or an identical dry-needle fenestration-procedure without coadministration of autologous blood. All participants received identical structured rehabilitation and were followed up at 2, 6, 12, and 26 weeks. Outcome measures included local foot pain, validated foot patient-reported outcome measures (Foot Function Index-revised, Manchester-Oxford Foot Questionnaire, Foot and Ankle Ability Measure), measures of general function and "ability" (EuroQol [EQ]-5D-5L, Oswestry Disability Index), specific measures of activity (International Physical Activity Questionnaire), sleep (Pittsburgh Sleep Quality Index), and mood (Hospital Anxiety and Depression Scale). There were no significant between-group differences seen at any time-point studied. There were a number of statistically significant within-group improvements for local foot pain and function in both groups comparing baseline/follow-up data. Overall, levels of pain improved by 25% by 6 weeks and by 50% at 6 months. There were improvements in some generalized function markers. Activity rates did not change, demonstrating that improvements in pain did not necessarily influence physical activity. Coadministration of 3 mL of autologous blood had no additional effect compared to a dry-needling procedure alone for patients with chronic plantar fasciitis. Level I, double-blinded randomized controlled trial.


Current status and future prospects for electronic point-of-care clinical decision support in diabetes care.
Early efforts to use point-of-care clinical decision support (CDS) were limited to the use of prompts and reminders, which improved test ordering but not intermediate outcomes of care, such as glucose, blood pressure, or lipid levels. More sophisticated diabetes CDS tools are now available that use electronic medical record data to provide patient-specific advice on medication use on the basis of previous treatment, distance from goal, and other clinical data. These tools have shown modest but significant improvement in glucose and blood pressure control. Promising next-generation developments will include prioritizing clinical actions that have maximum benefit to a given patient at the point of care and developing effective methods to communicate CDS information to patients to better incorporate patient preferences in care decisions.


A 3D global-to-local deformable mesh model based registration and anatomy-constrained segmentation method for image guided prostate radiotherapy.
In the external beam radiation treatment of prostate cancers, successful implementation of adaptive radiotherapy and conformal radiation dose delivery is highly dependent on precise and expeditious segmentation-and registration of the prostate volume between the simulation and the treatment images. The purpose of this study is to develop a novel, fast, and accurate segmentation and registration method to increase the computational efficiency to meet the restricted clinical treatment time requirement in image guided radiotherapy. The method developed in this study used soft tissues to capture the transformation between the 3D planning CT (pCT) images and 3D cone-beam CT (CBCT) treatment images. The method incorporated a global-to-local deformable mesh model based registration framework as well as an automatic anatomy-constrained robust active shape model (ACRASM) based segmentation algorithm in the 3D CBCT images. The global registration was based on the mutual information method, and the local registration was to minimize the Euclidian distance of the corresponding nodal points from the global transformation of deformable mesh models, which implicitly used the information of the segmented target volume. The method was applied on six data sets of prostate cancer patients. Target volumes delineated by the same radiation oncologist on the pCT and CBCT were chosen as the benchmarks and were compared to the segmented and registered results. The distance-based and the volume-based estimators were used to quantitatively evaluate the results of segmentation and registration. The ACRASM segmentation algorithm was compared to the original active shape mode (ASM) algorithm by evaluating the values of the distance-based estimators. With respect to the corresponding benchmarks, the mean distance ranged from -0.85 to 0.84 mm for ACRASM and from -1.44 to 1.17 mm for ASM. The mean absolute distance ranged from 1.77 to 3.07 mm for ACRASM and from 2.45 to 6.54 mm for ASM. The volume overlap ratio ranged from 79% to 91% for ACRASM and from 44% to 80% for ASM. These data demonstrated that the segmentation results of ACRASM were in better agreement with the corresponding benchmarks than those of ASM. The developed registration algorithm was quantitatively evaluated by comparing the registered target volumes from the pCT to the benchmarks on the CBCT. The mean distance and the root mean square error ranged from 0.38 to 2.2 mm and from 0.45 to 2.36 mm, respectively, between the CBCT images and the registered pCT. The mean overlap ratio of the prostate volumes ranged from 85.2% to 95% after registration. The average time of the ACRASM-based segmentation was under 1 min. The average time of the global transformation was from 2 to 4 min on two 3D volumes and the average time of the local transformation was from 20 to 34 s on two deformable superquadrics mesh models. A novel and fast segmentation and deformable registration method was developed to capture the transformation between the planning and treatment images for external beam radiotherapy of prostate cancers. This method increases the computational efficiency and may provide foundation to achieve real time adaptive radiotherapy.


[Circulating citrulline levels: a biomarker for intestinal functionality assessment].
Circulating citrulline is emerging as an innovating biomarker candidate for assessment of intestinal function. Amino acid synthesized by enterocytes of intestinal mucosal, citrulline is not included in proteins or nutrition products and is a precursor for production of arginine by the kidney. Plasma citrulline is, in clinical situation, an established biomarker of enterocyte functional metabolic mass (trophicity) in children and in adult patients due to its high relation to active functional small bowel remnant length in intestinal diseases (short bowel, extensive enteropathies, intestinal toxicity of chemotherapy and radiotherapy. Plasma citrulline concentration (30-50 μmol/L), independent of nutritional status, if less than 10 μmol/L can give an objective threshold for nutrition parenteral use in case of intestinal failure due to enterocyte abnormalities or lack. Its regular dosage allows the monitoring of intestinal function except in case of significant renal failure.


Oxidative neurotoxicity in rat cerebral cortex neurons: synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3.
Oxidative stress in the brain has been increasingly associated with the development of numerous human neurological diseases. Microglia, activated upon neuronal injury or inflammatory stimulation, are known to release superoxide anion (*O(2) (-)), hydrogen peroxide (H(2)O(2)), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and *O(2) (-), forming the toxic peroxynitrite (ONOO(-)), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H(2)O(2) and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H(2)O(2) plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H(2)O(2) and NO, we monitored the production of ONOO(-)and reactive oxygen species (ROS) throughout the experiments. Results indicated that the NO donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and H(2)O(2) by themselves elicited neuronal death in a concentration- and time-dependent manner. Sublytic concentrations of H(2)O(2) plus SNAP were sufficient to induce neuronal apoptosis as determined by DNA laddering and fluorescent staining of apoptotic nuclei. Transient ONOO(-)increase was accompanied by rapid H(2)O(2) decay and NO production, whereas ROS slowly decreased following treatment. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation and the cleavage of caspase-3 were observed. Conversely, inhibition of p38 MAPK and caspase-3 significantly reduced apoptotic death induced by H(2)O(2) plus SNAP. These data suggest that H(2)O(2) and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.


Active therapy and models of care for adolescents and young adults with cancer.
The reduction in the cancer mortality rate in adolescents and young adults (AYA) with cancer has lagged behind the reduction noted in children and older adults. Studies investigating reasons for this are limited but causes appear to be multifactorial. Host factors such as developmental stage, compliance, and tolerance to therapy; provider factors such as lack of awareness of cancer in AYA and referral patterns; differences in disease biology and treatment strategies; low accrual onto clinical trials; and lack of psychosocial support and education programs for AYA all likely play a role. Recommendations for change from a recent international workshop include education of physicians and patients concerning AYA cancer, improved cooperation between pediatric and adult centers, age-appropriate psychosocial support services, programs to help AYA with issues relevant to them, dedicated AYA hospital space, improved accrual to clinical trials, the use of technology to educate patients and enhance communication between patients and the health care team, and ensuring that resident and fellowship training programs provide adequate education in AYA oncology. The longer term goal is to develop AYA oncology into a distinct subspecialist discipline within oncology. The ideal model of care would incorporate medical care, psychosocial support services, and a physical environment that are age-appropriate. When this is not feasible, the development of "virtual units" connecting patients to the health care team or a combination of physical and virtual models are alternative options. The assessment of outcome measures is necessary to determine whether the interventions implemented result in improved survival and better quality of life, and are cost-effective.


The effects of photoperiod and lid suture on eye growth in chickens.
Three models of postnatal eye enlargement in leghorn chicks (surgical fusion of the eyelids, MES; exposure to continuous light, 24L; prolonged darkness, OL) were characterized on a morphologic and temporal basis, and a relationship between photoperiod and eye growth was described. While pronounced enlargement of the eye was evident in the OL and MES groups after 6 wk, a 15-wk experimental period was necessary to produce significant (P less than 0.05) eye enlargement under 24L. This enlargement was unaffected by pinealectomy and was characterized by increased equatorial diameter and decreased axial length. The macrophthalmos resulting from both MES and OL was characterized by increases in absolute and relative eye weights, axial length, and equatorial diameter. The MES eyes, however, showed a pronounced bulging of the cornea and increased anterior chamber depth and equatorial diameter, while those from the OL group had a flattened cornea and decreased anterior chamber depth. Finally, a relationship between photoperiod and eye growth was established and was best described by an inverse, continuous semilogarithmic function.


Cisplatin and 5-FU infusion chemotherapy in advanced, recurrent cancer of the head and neck: an Eastern Cooperative Oncology Group Pilot Study.
Thirty-four patients with advanced, recurrent head and neck cancer were treated with cisplatin (100 mg/m2 on Day 1) and continuous-infusion 5-FU (1.0 g/m2/24 hours on Days 1-5) every 3-4 weeks. All but one patient had failed prior radiation therapy or surgery; 27 had failed both. Two patients were not evaluable for response because of death within the first 2 weeks from unrelated heart disease. Among 30 patients with squamous cell carcinoma, five achieved complete response (CR) (17%) and 13 achieved partial response (PR) (43%). Durations of response for patients with a CR and PR were 10.4 and 3.1 months, respectively. Median time to disease progression for all patients was 4.5 months and median survival was 9.1 months. Median survival times for all responders and for complete responders and partial responders were 12.5, 14.2, and 10 months, respectively. One additional patient with an adenocarcinoma failed to respond, while a second with an adenoid cystic carcinoma achieved a PR for 3.4 months. Toxicity was moderate: seven patients experienced Eastern Cooperative Oncology Group grade 3 mucositis, and 11 patients had grade 3-4 hematologic toxicity. There was one treatment-related death due to nephrotoxicity. This study supports other studies that show a relatively high degree of activity of cisplatin and continuous-infusion 5-FU in advanced head and neck cancer.


PANNA 2.0: Efficient neural network interatomic potentials and new architectures.
We present the latest release of PANNA 2.0 (Properties from Artificial Neural Network Architectures), a code for the generation of neural network interatomic potentials based on local atomic descriptors and multilayer perceptrons. Built on a new back end, this new release of PANNA features improved tools for customizing and monitoring network training, better graphics processing unit support including a fast descriptor calculator, new plugins for external codes, and a new architecture for the inclusion of long-range electrostatic interactions through a variational charge equilibration scheme. We present an overview of the main features of the new code, and several benchmarks comparing the accuracy of PANNA models to the state of the art, on commonly used benchmarks as well as richer datasets.


Genistein and cancer: current status, challenges, and future directions.
Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources, such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer, focusing on its chemical features, plant food sources, bioavailability, and safety.


Doppler sonography characteristics of vertebrobasilar circulation in patients with Parkinson's disease.
The objective of the study was to analyze the doppler sonography findings of vertebrobasilar circulation (VB) in patients with Parkinson's disease. 40 patients were analyzed (25 men's and 15 women) with Parkinson's disease, average age was 61.9 years (SD=11.43), treated at the Clinic for Neurology in Tuzla. Device for doppler sonography was Multidop x 4. Doppler sonography findings of VB circulation were analyzed in order to computerized tomography (CT) findings of the brain (with or without ischemic lacunar lesions) and in order to presence of postural disturbances as one of dominant Parkinson's disease symptoms during actual hospitalization. Our results suggest that vertebrobasilar insufficiency is more frequent in patients with Parkinson's disease (no matter of type) and postural disturbances as a dominant symptom comparing to group of Parkinson's disease patients without postural disturbances. These results implicate the importance of doppler sonography findings of vertebrobasilar circulation in patients with Parkinson's disease and possibility of considering role of vertebrobasilar insufficiency in development of postural disturbances.


Self-renewal and differentiation capacity of urine-derived stem cells after urine preservation for 24 hours.
Despite successful approaches to preserve organs, tissues, and isolated cells, the maintenance of stem cell viability and function in body fluids during storage for cell distribution and transportation remains unexplored. The aim of this study was to characterize urine-derived stem cells (USCs) after optimal preservation of urine specimens for up to 24 hours. A total of 415 urine specimens were collected from 12 healthy men (age range 20-54 years old). About 6 × 10(4) cells shed off from the urinary tract system in 24 hours. At least 100 USC clones were obtained from the stored urine specimens after 24 hours and maintained similar biological features to fresh USCs. The stored USCs had a "rice grain" shape in primary culture, and expressed mesenchymal stem cell surface markers, high telomerase activity, and normal karyotypes. Importantly, the preserved cells retained bipotent differentiation capacity. Differentiated USCs expressed myogenic specific proteins and contractile function when exposed to myogenic differentiation medium, and they expressed urothelial cell-specific markers and barrier function when exposed to urothelial differentiation medium. These data demonstrated that up to 75% of fresh USCs can be safely persevered in urine for 24 hours and that these cells stored in urine retain their original stem cell properties, indicating that preserved USCs could be available for potential use in cell-based therapy or clinical diagnosis.


Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation.
In pancreatic ductal adenocarcinoma (PDAC), the fibroblast growth factor receptor 1 (FGFR-1) IIIb isoform correlates with the inhibition of cancer cell proliferation, migration, and invasion, whereas FGFR-1 IIIc enhances cancer cell proliferation. The FGFR-2 IIIb isoform is expressed in PDAC, and its expression correlates with increased venous invasion. We examined the role of FGFR-2 IIIc in PDAC. FGFR-2 IIIc was expressed in all six pancreatic cancer cell lines examined and was highest in PANC-1 cells. FGFR-2 IIIc was abundant in the cancer cells from 83 of 117 PDAC cases, which correlated with decreased duration to development of liver metastasis after surgery. FGFR-2 IIIc-transfected cells exhibited increased proliferation in vitro and formed larger subcutaneous and orthotopic tumors, the latter producing more liver metastases. Moreover, FGF-2 exerted a more rapid stimulatory effect on the levels of phosphorylated extracellular signal-regulated kinase (p-ERK) in FGFR-2 IIIc stably transfected PANC-1 cells, compared with control cells. FGFR-2 IIIc-transfected cells also formed more spheres and contained more side population cells. Suppression of FGFR-2 IIIc expression inhibited the proliferation of PANC-1 cells, whereas an anti-FGFR-2 IIIc antibody inhibited the proliferation and migration of PANC-1 cells. Thus, high FGFR-2 IIIc levels in PDAC contribute to disease aggressiveness and confer to pancreatic cancer cells features suggestive of cancer stem cells, indicating that FGFR-2 IIIc may be a novel and important therapeutic target in PDAC.


Elucidating Lithium Alloying-Induced Degradation Evolution in High-Capacity Electrodes.
Alloy electrode materials offer high capacity in lithium-ion batteries; however, they exhibit rapid degradation resulting in particle disintegration and electrochemical performance decay. In this study, the evolution of lithium alloying-induced degradation due to electrochemomechanical interactions is examined based on a multipronged electrochemical and microstructural analysis. Copper-tin (Cu6Sn5) is chosen as an exemplary alloy electrode material. Electrodes with compositional variations were fabricated, and electrochemical performance was examined under varying conditions including voltage window, C-rate, and short- and long-term cycling. Morphology and composition analyses of pristine and cycled electrodes were conducted using micrography and spectroscopy techniques. Alloying-induced electrode microstructural evolution was probed using X-ray microtomography. The rapid capacity fading was found to be caused by mechanical degradation of the electrode. Driving the electrode to a lower potential ( E ≈ 0.2 V vs Li/Li+) induced Li-Sn alloy formation and provided the characteristic large capacity; however, this led to a large volume expansion and active particle cracking and disintegration. Copper expulsion was found to be a consequence of the alloy formation; however, it was not the primary contributor to the dramatic electrochemical performance decay.


Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.
Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.


Plasma prekallikrein: isolation, characterization, and mechanism of activation.
The precursor of the kinin-forming enzyme, prekallikrein, was isolated from rabbit plasma protected from activation during preparatory procedures. Prekallikrein was shown to be a 4.5S gamma(1)-glycoprotein with an isoelectric point of 5.9 and a mol wt of 99,900. The proenzyme was activated at neutral pH by an enzyme from rabbit or human plasma we have termed prekallikrein activator (PKA) or by trypsin. Prekallikrein was activated by PKA by a process of enzymatic scission. This resulted in the appearance of two fragments; the larger of these possessed kallikrein activity.


Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource.
This study sought to characterize transformation incidence and outcome for patients with follicular lymphoma (FL) in a prospective observational series begun after diffusion of rituximab use. Patients with newly diagnosed FL were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2009. Patients were actively followed for re-treatment, clinical or pathologic transformation, and death. Risk of transformation was analyzed via time to transformation by using death as a competing risk. In all, there were 631 patients with newly diagnosed grade 1 to 3a FL who had a median age at enrollment of 60 years. At a median follow-up of 60 months (range, 11 to 110 months), 79 patients had died, and 60 patients developed transformed lymphoma, of which 51 were biopsy proven. The overall transformation rate at 5 years was 10.7%, with an estimated rate of 2% per year. Increased lactate dehydrogenase was associated with increased risk of transformation. Transformation rate at 5 years was highest in patients who were initially observed and lowest in patients who initially received rituximab monotherapy (14.4% v 3.2%; P = .021). Median overall survival following transformation was 50 months and was superior in patients with transformation greater than 18 months after FL diagnosis compared with patients with earlier transformation (5-year overall survival, 66% v 22%; P < .001). Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation and may be lower than reported in older series. Post-transformation prognosis is substantially better than described in older series. Initial management strategies may influence the risk of transformation.


Biomechanics and the thermotolerance of development.
Successful completion of development requires coordination of patterning events with morphogenetic movements. Environmental variability challenges this coordination. For example, developing organisms encounter varying environmental temperatures that can strongly influence developmental rates. We hypothesized that the mechanics of morphogenesis would have to be finely adjusted to allow for normal morphogenesis across a wide range of developmental rates. We formulated our hypothesis as a simple model incorporating time-dependent application of force to a viscoelastic tissue. This model suggested that the capacity to maintain normal morphogenesis across a range of temperatures would depend on how both tissue viscoelasticity and the forces that drive deformation vary with temperature. To test this model we investigated how the mechanical behavior of embryonic tissue (Xenopus laevis) changed with temperature; we used a combination of micropipette aspiration to measure viscoelasticity, electrically induced contractions to measure cellular force generation, and confocal microscopy to measure endogenous contractility. Contrary to expectations, the viscoelasticity of the tissues and peak contractile tension proved invariant with temperature even as rates of force generation and gastrulation movements varied three-fold. Furthermore, the relative rates of different gastrulation movements varied with temperature: the speed of blastopore closure increased more slowly with temperature than the speed of the dorsal-to-ventral progression of involution. The changes in the relative rates of different tissue movements can be explained by the viscoelastic deformation model given observed viscoelastic properties, but only if morphogenetic forces increase slowly rather than all at once.


New drug development in non-Hodgkin lymphomas.
The non-Hodgkin lymphomas (NHL) are characterized by initial responsiveness to a variety of chemotherapeutic regimens. Nevertheless, most patients progress and die from their disease. A number of new agents with unique mechanisms of action are in clinical development. Agents that are currently considered to be the most promising include those that induce apoptosis; those that interfere with cell cycling, tumor-associated angiogenesis, farnesylation of the Ras gene, and histone deacetylase; and those that inhibit the proteasome, among others. Increasing insights into the differences between tumors and among patients will lead to more individualized therapeutic strategies using agents directed at specific genetic and immunologic targets. More rapid accrual to high-quality clinical studies will facilitate dissemination of new agents to patients and lead to an increased cure rate for NHL.


Catastrophic antiphospholipid syndrome: atypical presentation in the setting of chronic graft versus host disease: case report and review of the literature.
A 44-year-old female developed a catastrophic thrombotic syndrome following allogeneic stem cell transplantation for acute lymphoblastic leukemia. In the context of chronic graft versus host disease, she developed a lethal multi-system thrombotic state as evidenced by stroke, renal failure and cardiac thrombi in association with elevated anticardiolipin antibody. The case is discussed in the framework of the existing literature and derives clinical practice recommendations for this rare but clinically devastating entity.


Gait Disorder among Elderly People, Psychomotor Disadaptation Syndrome: Post-Fall Syndrome, Risk Factors and Follow-Up - A Cohort Study of 70 Patients.
Falls among older people are a major health issue and the first cause of accidental death after 75 years of age. Post-fall syndrome (PFS) is commonly known and yet poorly studied. Identify risk factors for PFS and do a follow-up 1 year later. We included all patients over 70 years of age hospitalized after suffering a fall in a case-control study, and then followed them in a cohort study. PFS was retained in case of functional mobility decline (transferring, walking) occurring following a fall in the absence of an acute neurological, orthopedic or rheumatic pathology directly responsible for the decline. The data initially collected were: clinical (anamnestic, emergency and departmental/ward evolution, medical history, lifestyle, treatments, clinical examination items); and imaging if the patient had been subjected to brain imaging in the last 3 years prior to inclusion. Regarding the follow-up at 1 year, we collected from the general physician the occurrence and the characteristics of new falls, functional mobility assessment, hospitalization and death. Inclusion took place from March 29, 2016 to June 7, 2016 and follow-up until June 30, 2017. We included 70 patients. A total of 29 patients exhibited a PFS (41.4 %). Risk factors for PFS included age, walking disorder prior to the fall, the use of a walking aid prior to the fall, no unaccompanied outdoor walk in the week before the fall, visual impairment making close reading impossible, stiffness in ankle dorsiflexion, grip strength and the fear of falling. Among patients with PFS, 52.9% could still perform a transfer at 1 year and 64.7% could still walk against 80.7% and 85.2%, respectively, for patients without PFS. The study showed the existence of body functions/structure impairments and activity limitations prior to the fall among patients exhibiting a PFS. This suggests the existence of a pre-fall syndrome, i.e., a psychomotor disadaptation syndrome existing prior to the fall. Among the 8 risk factors, fear of falling, vision impairment and muscle strength could be targeted for improvement. The diagnosis of PFS could be a marker of loss of functional mobility at 1 year.


Differences in clamp loader mechanism between bacteria and eukaryotes.
Clamp loaders are pentameric ATPases that place circular sliding clamps onto DNA, where they function in DNA replication and genome integrity. The central activity of a clamp loader is the opening of the ring-shaped sliding clamp, and the subsequent binding to primer-template (p/t)-junctions. The general architecture of clamp loaders is conserved across all life, suggesting that their mechanism is retained. Recent structural studies of the eukaryotic clamp loader Replication Factor C (RFC) revealed that it functions using a crab-claw mechanism, where clamp opening is coupled to a massive conformational change in the loader. Here we investigate the clamp loading mechanism of the E. coli clamp loader at high resolution using cryo-electron microscopy (cryo-EM). We find that the E. coli clamp loader opens the clamp using a crab-claw motion at a single pivot point, whereas the eukaryotic RFC loader uses motions distributed across the complex. Furthermore, we find clamp opening occurs in multiple steps, starting with a partly open state with a spiral conformation, and proceeding to a wide open clamp in a surprising planar geometry. Finally, our structures in the presence of p/t-junctions illustrate how clamp closes around p/t-junctions and how the clamp loader initiates release from the loaded clamp. Our results reveal mechanistic distinctions in a macromolecular machine that is conserved across all domains of life.


Mediastinal endodermal sinus tumour: surgical role in chemotherapy resistant cases.
We report two cases of aggressive mediastinal endodermal sinus tumours (EST) detected incidentally on a chest radiograph. The patients were being investigated for minor chest complaints. After three courses of cisplatin-based chemotherapy the tumour marker levels declined. However, the tumour size continued to increase. Complete surgical removal was possible in one case and significant reduction in tumour mass was achieved in the other. Reduction in the viable, tumour tissue load made the residual tumour sensitive to postoperative chemotherapy. It is important to be aware of endodermal sinus tumours refractory to chemotherapy which may require early surgical intervention.


Cytotoxic and mutagenic evaluation of extracts from plant species of the Miconia genus and their influence on doxorubicin-induced mutagenicity: an in vitro analysis.
The Miconia genus, a plant widely used for medicine, occurs in tropical America and its extracts and isolated compounds have demonstrated antibiotic, antitumoral, analgesic and antimalarial activities. However, no study concerning its genotoxicity has been conducted and it is necessary to determine its potential mutagenic effects to develop products and chemicals from these extracts. This study assessed the cytotoxicity, mutagenicity and the protective effects of methanolic extracts from Miconia species on Chinese hamster lung fibroblast cell cultures (V79). The cytotoxicity was evaluated using a clonogenic assay. Cultures exposed to the extract of Miconia albicans up to a concentration of 30 μg/mL, M. cabucu up to 40 μg/mL, M. albicans up to 40 μg/mL and M. stenostachya up to 60 μg/mL exhibited a cytotoxic effect on the cells. The clonogenic assay used three non-cytotoxic concentrations (5, 10 and 20 μg/mL) to evaluate mutagenicity and antimutagenicity of the extracts. Cultures were treated with these three extract concentrations (mutagenicity test) or the extract associated with doxorubicin (DXR) (antimutagenicity test) in three protocols (pre-, simultaneous and post-treatments). Distilled water and DXR were used as negative and positive controls, respectively. In the micronucleus (MN) test, a significant reduction was observed in MN frequency in cultures treated with DXR and extracts compared to those receiving only DXR; a significant reduction was also observed for the presence of mutagenicity in all treatments. This study confirmed the safe use of Miconia extracts at the concentrations tested and reinforced the therapeutic properties previously described for Miconia species by showing their protective effects on doxorubicin-induced mutagenicity.


Online health information on sinonasal inverted papillomas: An assessment on readability and quality.
Sinonasal inverted papilloma (IP) is a rare but serious diagnosis, with a paucity of patient-centred information regarding this condition. As more patients are seeking healthcare information online, the quality and comprehensibility of this information becomes ever more important. The aim of the study was to investigate the readability and quality of websites on inverted papilloma. The term IP and seven of its synonyms were inputted into the three of the most commonly used search engines in the English-speaking world (Google, Yahoo and Bing). The first 20 results returned for each search term were then screened with our exclusion criteria. The remaining websites were assessed for their readability using the using the Flesch Reading Ease Score (FRES) and average grade level (AGL). Quality was assessed using the DISCERN questionnaire. Of the 480 websites returned using our search strategy, 410 were excluded using our screening criteria. Removal of duplicates from the remaining 70 websites left 14 for inclusion in the final analysis. The mean FRES score of the remaining websites was 30.5 ± 10 and the mean AGL was 15.2 ± 1.1, corresponding to a reading age of a 21-year-old. The median DISCERN score was 33.5 (30.5-36.5), a score which falls within the 'poor quality' range. The readability and quality of online patient information on IP is far below the expected standard. Healthcare providers have a responsibility to direct patients to appropriate sources of information or consider producing new material should a lack of appropriate sources exist.


Evaluation of methods for generative modeling of cell and nuclear shape.
Cell shape provides both geometry for, and a reflection of, cell function. Numerous methods for describing and modeling cell shape have been described, but previous evaluation of these methods in terms of the accuracy of generative models has been limited. Here we compare traditional methods and deep autoencoders to build generative models for cell shapes in terms of the accuracy with which shapes can be reconstructed from models. We evaluated the methods on different collections of 2D and 3D cell images, and found that none of the methods gave accurate reconstructions using low dimensional encodings. As expected, much higher accuracies were observed using high dimensional encodings, with outline-based methods significantly outperforming image-based autoencoders. The latter tended to encode all cells as having smooth shapes, even for high dimensions. For complex 3D cell shapes, we developed a significant improvement of a method based on the spherical harmonic transform that performs significantly better than other methods. We obtained similar results for the joint modeling of cell and nuclear shape. Finally, we evaluated the modeling of shape dynamics by interpolation in the shape space. We found that our modified method provided lower deformation energies along linear interpolation paths than other methods. This allows practical shape evolution in high dimensional shape spaces. We conclude that our improved spherical harmonic based methods are preferable for cell and nuclear shape modeling, providing better representations, higher computational efficiency and requiring fewer training images than deep learning methods. All software and data is available at http://murphylab.cbd.cmu.edu/software. Supplementary data are available at Bioinformatics online.


Subtalar joint arthrodesis using a single lag screw.
This study tested the hypotheses that fusing the subtalar joint with a single lag screw from the posteroinferior calcaneus to the anterior talar neck is an effective technique and that factors affecting the time to fusion can be identified. Between October, 1995, and July, 2002, the senior author (RAM) performed 101 isolated subtalar arthrodeses using a technique of single lag-screw fixation from posteroinferior to anterosuperior across the posterior facet of the subtalar joint combined with the application of an autograft taken from the floor of the sinus tarsi and anterior process. The average patient age was 52 (range 17 to 82) years. There were 52 women (53 arthrodeses) and 48 men (48 arthrodeses). Eight of 101 (8%) arthrodeses were revisions. The indications included posttraumatic arthritis (45), posterior tibial tendon dysfunction (18), failed prior ankle joint fusion (14), idiopathic disorders (12), hindfoot coalition (7), rheumatoid arthritis (3), and Charcot-Marie-Tooth disease (2). Fifteen of 101 patients (15%) smoked an average of 0.9 +/- 0.5 pack of cigarettes per day. Two of 101 joints did not fuse, resulting in an overall fusion rate of 98%. The average time to fusion was 12.3 +/- 3.4 weeks. The presence of a prior ankle fusion significantly prolonged the time to fusion of the subtalar joint (11.9 +/- 2.3 vs. 14.9 +/- 7.0, p = .003). Other factors, including smoking, revision surgery, patient age, and patient sex, did not affect time to fusion. The fixation screw was removed in 13 of 101 (13%) joints at an average of 8.8 +/- 0.5 months. Using a single 7.0-mm lag screw across the posterior facet of the subtalar joint results in fusion of the subtalar joint in 98% of patients. A prior ankle arthrodesis delays the time to fusion of the subtalar joint by 3 weeks. This is a simple and reliable technique for achieving fusion of the subtalar joint.


The decrease of neuromuscular transmission by adenosine depends on previous neuromuscular depression.
The action of adenosine (0.5 mM) on neuromuscular transmission has been studied in the presence of progressively blocking concentrations of tubocurarine, tetrodotoxin, and high Mg2+/low Ca2+ solutions. Adenosine enhanced the inhibitory effects elicited either by tubocurarine (4 X 10(-7) - 12 X 10(-7) M), high Mg2+(5 - 11 mM) or low CA2+(0.8 - 0.3 mM) concentrations. The effect of adenosine depended upon the size of the previous neuromuscular inhibition. In the presence of tubocurarine, the inhibitory effects of adenosine were greater at room temperature than at 37 degrees C; however, adenosine was more potent at 37 degrees C than at room temperature in solutions with high Mg2+ or low Ca2+ concentrations. Adenosine did not change the inhibitory effects of tetrodotoxin either at 37 degrees C or at room temperature. These findings suggest that the partial neuromuscular blockade, for the inhibitory action of adenosine to be apparent, has to take place either postsynaptically via the blockade of ACh receptors or presynaptically at the nerve endings through a decrease in the evoked output of the transmitter. Since ATP and/or adenosine are released at the neuromuscular junction, a potential involvement of these substances in conditions with impairment of neuromuscular transmission (e.g. myasthenia gravis) is discussed.


Stakeholder views on returning research results.
While the disclosure of research findings is relevant to all types of biomedical research, it has garnered particular attention with respect to genetics and genomics research due to some of the unique aspects of the data and the high public profile of the field. In this chapter, we review the attitudes of stakeholders (research participants, policymakers, and researchers) to define areas of consensus regarding the issue of returning research results across and within groups. In addition to stakeholder attitudes about obligations and interest in research results, other major related issues related to returning research results, such as informed consent, communication of research results, and cost, are discussed. Given the consensus between stakeholders to return summary reports of a study's outcomes and individual research results of clinical significance, we conclude that the time has come to encourage, if not require, researchers to consider these issues in the developmental planning stages of a project and to plan and budget accordingly.