Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells.
Canonical Hedgehog (HH) signaling is characterized by Smoothened (Smo)-dependent activation of the transcription factors Gli1 and Gli2, which regulate HH target genes. In human colon carcinoma cells, treatment with the Gli small-molecule inhibitor GANT61 induces extensive cell death in contrast to the Smo inhibitor cyclopamine. Here we elucidate cellular events upstream of cell death elicited by GANT61, which reveal the basis for its unique cytotoxic activity in colon carcinoma cells. Unlike cyclopamine, GANT61 induced transient cellular accumulation at G(1)-S (24 hours) and in early S-phase (32 hours), with elevated p21(Cip1), cyclin E, and cyclin A in HT29 cells. GANT61 induced DNA damage within 24 hours, with the appearance of p-ATM and p-Chk2. Pharmacologic inhibition of Gli1 and Gli2 by GANT61 or genetic inhibition by transient transfection of the Gli3 repressor (Gli3R) downregulated Gli1 and Gli2 expression and induced γH2AX, PARP cleavage, caspase-3 activation, and cell death. GANT61 induced γH2AX nuclear foci, while transient transfection of Gli3R showed expression of Gli3R and γH2AX foci within the same nuclei in HT29, SW480, and HCT116. GANT61 specifically targeted Gli1 and Gli2 substantiated by specific inhibition of (i) direct binding of Gli1 and Gli2 to the promoters of target genes HIP1 and BCL-2, (ii) Gli-luciferase activity, and (iii) transcriptional activation of BCL-2. Taken together, these findings establish that inhibition of HH signaling at the level of the GLI genes downstream of Smo is critical in the induction of DNA damage in early S-phase, leading to cell death in human colon carcinoma cells.


Polyphenol-rich extracts from Solanum nigrum attenuated PKC alpha-mediated migration and invasion of hepatocellular carcinoma cells.
Solanum nigrum L. (SN) has exhibited multiple biological effects such as anti-inflammation and antiproliferation. Protein kinase C (PKC) regulates cellular functions including proliferation, migration, and invasion. In the present investigation, we demonstrated that 12-o-tetradecanoylphobor-13-acetate (TPA) and constitutively activated PKC alpha significantly increased migration and invasion of HepG2 cells, while treatment with water or polyphenol extracts of SN (SNWE or SNPE) attenuated TPA-induced migration and invasion. SNWE and SNPE reduced TPA-elicited PKC alpha expression in a dose-dependent manner and obviously inhibited TPA-induced phosphorylation of p38 and ERK, respectively. Constitutively activated PKC alpha (caPKC alpha) significantly reversed the inhibitory effects of SNWE and SNPE on ERK and p38 activation. However, the antimigration effect of SNWE and SNPE could not be abrogated by caPKC alpha. Our results revealed the antimigration and anti-invasion effects of both extracts derived from SN, which may act as a promising therapeutic agent for the treatment of hepatocellular carcinoma.


Methods and algorithms for optical coherence tomography-based angiography: a review and comparison.
Optical coherence tomography (OCT)-based angiography is increasingly becoming a clinically useful and important imaging technique due to its ability to provide volumetric microvascular networks innervating tissue beds in vivo without a need for exogenous contrast agent. Numerous OCT angiography algorithms have recently been proposed for the purpose of contrasting microvascular networks. A general literature review is provided on the recent progress of OCT angiography methods and algorithms. The basic physics and mathematics behind each method together with its contrast mechanism are described. Potential directions for future technical development of OCT based angiography is then briefly discussed. Finally, by the use of clinical data captured from normal and pathological subjects, the imaging performance of vascular networks delivered by the most recently reported algorithms is evaluated and compared, including optical microangiography, speckle variance,phase variance, split-spectrum amplitude decorrelation angiography, and correlation mapping. It is found that the method that utilizes complex OCT signal to contrast retinal blood flow delivers the best performance among all the algorithms in terms of image contrast and vessel connectivity. The purpose of this review is to help readers understand and select appropriate OCT angiography algorithm for use in specific applications.


Relapse of Rectal Cancer in an Anal Fistula: A Rare Case.
Colorectal cancer is the second most common cause of cancer-related death worldwide. It is well-known that metasta sis to the liver and lung and local recurrences can occur. Additionally, colorectal cancer occasionally metastasizes to other sites. Only a few reports of such metastases have been published and no definitive therapeutic strategies have been proposed for them. The case of a 77-year-old man who was diagnosed with rectal cancer is presented. Eighteen months after curative laparoscopic low anterior resection and D3 lymph node resection, an anal fistula metastasis was diagnosed by computed tomography and biopsy. After administering radiotherapy, percutaneous excision of the lesion. was performed. At 21 months from the surgery, the patient is healthy and no recurrence has been found. Metachronous metastasis of a colorectal cancer to an anal fistula is rare. Careful investigation and optimal treatment can result in a disease-free status.


Open trial of S-adenosylmethionine for treatment of depression.
Nine depressed inpatients completed trials with S-adenosylmethionine. Seven showed improvement or remission of their symptoms. As in European studies, no side effects were seen except the apparent induction of mania in two patients with bipolar disorder.


Neurology, psychiatry and the chess game: a narrative review.
The chess game comprises different domains of cognitive function, demands great concentration and attention and is present in many cultures as an instrument of literacy, learning and entertainment. Over the years, many effects of the game on the brain have been studied. Seen that, we reviewed the current literature to analyze the influence of chess on cognitive performance, decision-making process, linking to historical neurological and psychiatric disorders as we describe different diseases related to renowned chess players throughout history, discussing the influences of chess on the brain and behavior.


[Breast cancer with liver metastasis responsive to docetaxel: case report].
A 59-year-old female underwent mastectomy for right breast cancer in November 1992. She received tamoxifen and anthracycline-containing chemotherapy as adjuvant therapy. In and after September 1994, she developed loco-regional recurrences five times in total, each of which was treated with surgery and conventional combination chemotherapy. In April 1997, she developed liver metastasis, which was refractory to biochemical modulation therapy (low-dose cisplatin + 5-FU). We, therefore, treated her six times with docetaxel 80 mg, which resulted in partial response of the liver metastasis and brought about a marked decrease in serum CA15-3 levels. Adverse effects of docetaxel were grade 3 alopecia and leucocytopenia. She has been well without re-growth of the liver metastasis for over five months.


[System of pharmacologic control of histamine release by mast cells on exposure to different agents].
A scheme has been devised that makes it possible to assess a specific mechanism of action of any histamine-releasing agent. The scheme suggests a switch off of different stages of histamine secretion--interaction of a histamine liberator with surface cell receptors, entry of Ca2+ into the cell, temperature- and energy-dependent stages of histamine liberation, a stage that depends on microtubules, a system regulating histamine liberation with cyclic nucleotides. The scheme was made use of in clarification of the mechanism of histamine liberation on exposure of the mast cell to a specific antigen, to different doses of heavy metal salts, prednisolone and alkylating cross-binding agents.


[Epidemiologic characteristics of typhoid and paratyphoid fever on related drug resistance and molecular types regarding Salmonella typhi and S. paratyphi, in Jiangsu province].
To explore the distribution of prevalence rates of typhoid and paratyphoid, with drug resistance and molecular types of Salmonella (S.) typhi and S. paratyphi in Jiangsu province. Data, collected by the national infectious disease reporting system in Jiangsu province from 2007 to 2011, was analyzed. K-B method was used to test the sensibility to 9 kinds of antibiotics among 210 stains of S. typhi and S. paratyphi. 81 strains of S. typhi were classified by pulse-field gel electrophoresis (PFGE). The annual average incidence of typhoid and paratyphoid was 0.47 per 100 000 in the last five years, showing a decreasing trend. Highest incidence (1.70 per 100 000) was seen in the < 1 year age group, with S. typhi and S. paratyphi A accounted for 66.19% and 23.81% among the 210 stains. The rate of drug resistance to nalidixic acid appeared to be the highest as 66.19%. The drug resistant rates to 6 kinds of antibiotics were on average, lower than 10.00%. The multi-drug resistant rate of S. typhi and S. paratyphi was 30.00%. In the last 3 years, 37 types from 81 S. typhi strains had been classified into 4 clusters by PFGE. The predominant type was JPPX01. JS0027, accounted for 11.11%. JPPX01.JS0001 type had a specific regional distribution, but JPPX01.JS0014, JPPX01.JS0018 and JPPX01.JS0024 strains were widely spread. Results from the clustering analysis showed that cases in the 3 events tended to have a clustering nature. The morbidity of typhoid and paratyphoid was in a relatively low level in Jiangsu province. Although S. typhi and S. paratyphi were sensitive to most of the commonly used antibiotics, the resistance rates to some kinds of antibiotics were increasing. The distribution of typhoid was sporadic in Jiangsu and without the dominant strain, it was unlikely that typhoid could become epidemic in the future, in Jiangsu.


Exploring the potential of DNA vaccination.
DNA vaccines offer a unique means of stimulating and enhancing the immune response. Subjects are vaccinated with the gene for a particular antigen rather than with the antigen itself--the foreign protein that elicits the response is made intracellularly. This new type of gene therapy may not only extend the limits of immunoprotection but may also provide new insight into microbiologic and immunologic processes.


Comparing the variances of two independent groups.
Comparing the variances of two independent groups is a classic problem. Methods for comparing alternative measures of dispersion have been derived that perform well in simulations, but all methods for comparing variances have been found to be unsatisfactory in terms of Type I error probabilities or power. Currently, it appears that the most successful method, in terms of controlling the probability of a Type I error, is based on the so-called mean half-square successive difference statistic where a bootstrap is used to estimate its standard error, and a calibrated bootstrap is used to control the probability of a Type I error. But the mean half-square successive difference statistic is not permutation-invariant, and it is fairly evident that power can be relatively poor. A slight modification of the percentile bootstrap method for computing a 1 - alpha confidence interval for the difference between the variances is considered that corrects these problems.


Photo-responsive materials with strong cell trapping ability for light-guided manipulation of nonadherent cells.
We report a photo-cleavable material for tight trapping of nonadherent cells to substrate surfaces. Model immunocytes were selectively trapped in a non-irradiated area as single cells after the projection of a light pattern and withstood high-speed laminar flow, achieving light-guided cell release from the substrates.


Evaluation of gridded precipitation data for driving SWAT model in area upstream of Three Gorges Reservoir.
Gridded precipitation data are becoming an important source for driving hydrologic models to achieve stable and valid simulation results in different regions. Thus, evaluating different sources of precipitation data is important for improving the applicability of gridded data. In this study, we used three gridded rainfall datasets: 1) National Centers for Environmental Prediction-Climate Forecast System Reanalysis (NCEP-CFSR); 2) Asian Precipitation-Highly-Resolved Observational Data Integration Towards Evaluation (APHRODITE); and 3) China trend-surface reanalysis (trend surface) data. These are compared with monitoring precipitation data for driving the Soil and Water Assessment Tool in two basins upstream of Three Gorges Reservoir (TGR) in China. The results of one test basin with significant topographic influence indicates that all the gridded data have poor abilities in reproducing hydrologic processes with the topographic influence on precipitation quantity and distribution. However, in a relatively flat test basin, the APHRODITE and trend surface data can give stable and desirable results. The results of this study suggest that precipitation data for future applications should be considered comprehensively in the TGR area, including the influence of data density and topography.


Clinical pathology of non-freeze lamellar refractive keratoplasty.
We studied two corneal specimens obtained following corneal transplantation for loss of best corrected vision after planar lamellar refractive keratoplasty. The epithelium appeared slightly undifferentiated in both cases. Peripheral bends and occasional breaks were found in the periphery of Bowman's layer. In one case there were areas of subepithelial fibrosis as well as ultrastructural fractures in Bowman's layer. The keratocyte population appeared to be slightly decreased in one case. In both specimens the optical interface contained active fibroblasts in the periphery. The planar lamellar refractive keratoplasty technique theoretically eliminates many of the adverse morphologic features encountered following the standard Barraquer cryolathe techniques, but clinical studies will be needed to determine if this form of lamellar keratoplasty is clinically superior to currently practiced techniques.


Applying an intersectionality lens to the theoretical domains framework: a tool for thinking about how intersecting social identities and structures of power influence behaviour.
A key component of the implementation process is identifying potential barriers and facilitators that need to be addressed. The Theoretical Domains Framework (TDF) is one of the most commonly used frameworks for this purpose. When applying the TDF, it is critical to understand the context in which behaviours occur. Intersectionality, which accounts for the interface between social identity factors (e.g. age, gender) and structures of power (e.g. ageism, sexism), offers a novel approach to understanding how context shapes individual decision-making and behaviour. We aimed to develop a tool to be used alongside applications of the TDF to incorporate an intersectionality lens when identifying implementation barriers and enablers. An interdisciplinary Framework Committee (n = 17) prioritized the TDF as one of three models, theories, and frameworks (MTFs) to enhance with an intersectional lens through a modified Delphi approach. In collaboration with the wider Framework Committee, a subgroup considered all 14 TDF domains and iteratively developed recommendations for incorporating intersectionality considerations within the TDF and its domains. An iterative approach aimed at building consensus was used to finalize recommendations. Consensus on how to apply an intersectionality lens to the TDF was achieved after 12 rounds of revision. Two overarching considerations for using the intersectionality alongside the TDF were developed by the group as well as two to four prompts for each TDF domain to guide interview topic guides. Considerations and prompts were designed to assist users to reflect on how individual identities and structures of power may play a role in barriers and facilitators to behaviour change and subsequent intervention implementation. Through an expert-consensus approach, we developed a tool for applying an intersectionality lens alongside the TDF. Considering the role of intersecting social factors when identifying barriers and facilitators to implementing research evidence may result in more targeted and effective interventions that better reflect the realities of those involved.


Development of C5a receptor antagonists. Differential loss of functional responses.
C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation.


[Correlation between urinary sediment spectra and pathological patterns of renal biopsies].
To investigate the clinical value of urinary sediment analysis, a non-invasive diagnostic means, in the evaluation of pathological patterns of renal diseases. A total of 1 140 pairs of matched renal biopsies and fresh fasting morning urine specimens were collected from hospitalized patients in Peking University First Hospital. Their urinary sediments were examined with phase-contrast microscopy; the 24 h urine proteins were measured. Based on urinary sediment features combined with urine protein amount, the spectra of the urine sediments were classified into four types, Type I: hematuria-dominant, with multiple cells and casts; Type II: proteinuria-dominant, with hyaline or fine-granular casts but scanty cells; Type III: renal tubular epithelial cell(RTEC)-dominant, minor proteinuria; Type IV: non-specificurine sediments,minor proteinuria. According to the pathological lesions detected in renal biopsies, the renal diseases were classified into three patterns: proliferative glomerulopathy(P-GP), non-proliferative glomerulopathy (NP-GP) and tubulointerstitial nephropathy(TIN). The urinary sediment spectra of different pathological patterns and the correlation between urinary sediment types and pathological patterns were analyzed. Statistical analyses were performed using kappa test, and χ(2) test, and significance was accepted at P<0.05. (1) Of the 840 cases of matched urine samples and renal biopsies, 419 cases were diagnosed with P-GP; 375 cases with NP-GP; 46 cases with TIN respectively. (2) The spectra of urine sediments were associated with pathological patterns of the renal biopsies, and 84.0% of the patients with P-GP manifested type I urine sediments; 93.1% of the patients with NP-GP had type II urine sediments; 67.4% of the patients with TIN had type III urine sediments. (3) The correlation between the urinary sediment types and renal pathological patterns was validated in an additional 300 matched samples. The positive predictive values of urinary sediment spectra in predicting renal pathological lesions were 84.8% for typeI to P-GP, 86.0% for type II to NP-GP and 73.7% for type III to TIN, respectively. As a non-invasive diagnostic means, the urinary sediment analysis is valuable in the evaluation of pathological patterns of renal diseases.


Human factor VII deficiency caused by S339C mutation located adjacent to the specificity pocket of the catalytic domain.
This report documents our identification of a novel factor VII (FVII) gene mutation in a Japanese boy with FVII deficiency. The proband's FVII activity was 34% and his FVII antigen level was 40% of normal controls. DNA sequence analysis of the proband's FVII gene identified a C to G point mutation at nucleotide position 10 933 in exon 8, which results in the substitution of Cys (TGC) for Ser339 (TCC). Hinf I digestion results indicate the proband and his mother were heterozygous for the mutation. Both wild-type and mutant FVIIs were transiently expressed in COS-1 cells. FVII levels measured in the culture medium of FVII Ser339Cys mutants were markedly reduced as compared to those of cells with FVII wild-type. The amount of intracellular FVII in FVII Ser339Cys mutants was 80% of that in wild-type. In the wild-type FVII, Ser339 is juxtaposed to Asp338, which is positioned at the bottom of the substrate-binding pocket in the protease domain and located adjacent to FVII Cys340, that forms a disulphide bond with Cys368. We suspect that the creation of a novel unpaired cysteine through this mutation leads to abnormal disulphide bonding during protein folding, thereby reducing the secretion of FVII.


EPO adjustments in patients with elevated hemoglobin levels: provider practice patterns compared with recommended practice guidelines.
This study investigates provider practices regarding recombinant human erythropoietin (rHuEPO) dose when patient hemoglobin levels exceeded National Kidney Foundation-Dialysis Outcomes Quality Initiative target levels and reached 13 g/dL or greater (>or=130 g/L). The study population (N = 167,796) was hemodialysis patients prevalent on January 1, 2003, who were on renal replacement therapy at least 90 days with Medicare as primary payer and rHuEPO claims in 2 or more consecutive months. Patient characteristics were obtained from the Centers for Medicare & Medicaid Services (CMS) Medical Evidence Report, and comorbid conditions were determined from Medicare claims. Providers and rHuEPO claims were linked by using CMS-assigned provider numbers and the CMS Annual End-Stage Renal Disease Facility Survey. Between-provider differences in patient characteristics were examined by using chi-square test, and provider effect on appropriate response, by using logistic regression. DaVita's percentage of monthly claims for patients with hemoglobin levels of 13 g/dL or greater (>or=130 g/L; 16.7%) and mean monthly rHuEPO dose (54,299 units) were highest. Dialysis Clinic Inc's percentage of such claims (2.0%) and mean monthly dose (38,687 units) were lowest. Dialysis Clinic Inc, Fresenius, and Renal Care Group had the highest percentage of recommended dose adjustments (mean, 70% of units); hospital-based units had the lowest (59%). By adjusted odds ratio, adjustments were 20% more likely for Dialysis Clinic Inc, Fresenius, and Renal Care Group compared with DaVita, National Nephrology Associates, hospital-based units, and independents (17% to 28% less likely). rHuEPO dose reduction practices are dependent on specific dialysis providers and whether units are hospital based or independent.


Linear viscoelasticity and thermorheological simplicity of n-hexadecane fluids under oscillatory shear via non-equilibrium molecular dynamics simulations.
A small amplitude oscillatory shear flows with the classic characteristic of a phase shift when using non-equilibrium molecular dynamics simulations for n-hexadecane fluids. In a suitable range of strain amplitude, the fluid possesses significant linear viscoelastic behavior. Non-linear viscoelastic behavior of strain thinning, which means the dynamic modulus monotonously decreased with increasing strain amplitudes, was found at extreme strain amplitudes. Under isobaric conditions, different temperatures strongly affected the range of linear viscoelasticity and the slope of strain thinning. The fluid's phase states, containing solid-, liquid-, and gel-like states, can be distinguished through a criterion of the viscoelastic spectrum. As a result, a particular condition for the viscoelastic behavior of n-hexadecane molecules approaching that of the Rouse chain was obtained. Besides, more importantly, evidence of thermorheologically simple materials was presented in which the relaxation modulus obeys the time-temperature superposition principle. Therefore, using shift factors from the time-temperature superposition principle, the estimated Arrhenius flow activation energy was in good agreement with related experimental values. Furthermore, one relaxation modulus master curve well exhibited both transition and terminal zones. Especially regarding non-equilibrium thermodynamic states, variations in the density, with respect to frequencies, were revealed.


Personal resourcefulness: positive aspects of functioning in high-risk research.
This paper discusses theoretical and measurement issues involved in attaining a differentiated picture of the distribution of outcomes in subjects selected for their elevated risk for psychosis; these outcomes include positive adaptations as well as subtle expressions of psychopathology. Many at-risk subjects either do not break down or actually "prosper" in the face of risk factors, a problem that persists even when risk groups are defined with increasing selectivity. Although this phenomenon is often referred to as the problem of "false positives" in risk research, its implications are more far-reaching than simply defining a problem of low yield in prospective studies.


Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers.
This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).


A Chemogenomic Screening Platform Used to Identify Chemotypes Perturbing HSP90 Pathways.
Compounds that modulate the heat shock protein (HSP) network have potential in a broad range of research applications and diseases. A yeast-based liquid culture assay that measured time-dependent turbidity enabled the high-throughput screening of different Saccharomyces cerevisae strains to identify HSP modulators with unique molecular mechanisms. A focused set of four strains, with differing sensitivities to Hsp90 inhibitors, was used to screen a compound library of 3680 compounds. Computed turbidity curve functions were used to classify strain responses and sensitivity to chemical effects across the compound library. Filtering based on single-strain selectivity identified nine compounds as potential heat shock modulators, including the known Hsp90 inhibitor macbecin. Haploid yeast deletion strains (360), mined from previous Hsp90 inhibitor yeast screens and heat shock protein interaction data, were screened for differential sensitivities to known N-terminal ATP site-directed Hsp90 inhibitors to reveal functional distinctions. Strains demonstrating differential sensitivity (13) to Hsp90 inhibitors were used to prioritize primary screen hit compounds, with NSC145366 emerging as the lead hit. Our follow-up biochemical and functional studies show that NSC145366 directly interacts and inhibits the C-terminus of Hsp90, validating the platform as a powerful approach for early-stage identification of bioactive modulators of heat shock-dependent pathways.


Ovarian reserve markers and endocrine profile during oral contraception: Is there a link between the degree of ovarian suppression and AMH?
The ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) are suppressed in varying degree during the use of combined oral contraceptives (COC). Further, long-term use of COC can mask a condition of premature ovarian insufficiency. A desirable clinical tool that could distinguish true low ovarian reserve markers from COC-induced low levels during use of COC is warranted. The aim of this multicenter study including 235 COC users was to assess whether low age-adjusted AMH levels during COC use were linked to concomitant low levels of LH, FSH, estradiol and androgens - as a potential future tool to differentiate between 'false', COC-induced low AMH levels vs. true low AMH. Study population and methods: In total, 235 COC users from the general population aged 19-40 years were included. AMH, AFC and a reproductive hormonal profile were measured during COC intake. Age-adjusted AMH levels (Z-scores) were calculated from a comparison group of 983 non-users of COC. Differences in hormonal profile were tested between women with low versus high age-adjusted AMH-quartiles based on non-parametric Wilcoxon rank sum tests. The outcomes of interest were levels of gonadotropins, estradiol and androgens according to the four the age-adjusted AMH quartiles to find out if women with low age-adjusted AMH levels had a stronger gonadotropin suppression compared with women with higher age-adjusted AMH levels. Mean age of COC users was 30.2 years (SD 3.8), median AMH 14 pmol/l (inter-quartile range (IQR) 8.7-23)), median AFC 16 (IQR 11-25). We found no significant differences across the age-adjusted AMH quartiles in either the levels of gonadotropins, estrogens or androgens, respectively. Thus, the degree of suppression of FSH, LH, androgens and estradiol are unlikely to be a useful tool to differentiate between false low and true low ovarian reserve markers during COC use. Presently, there seems to be no alternative to withdrawal of the COC and to re-test the ovarian reserve after 2-3 months. Trial registration Trial no. NCT02785809 (www.clinicaltrials.gov).


Effect of varying protein and energy densities in complete rations fed to cows in first lactation.
Sixty-three Holstein cows in first lactation were allotted randomly at 28 days postpartum to receive one of nine rations in a 3 X 3 factorial design. Rations had crude protein 12, 15, or 18% in each of three energy densities from ratios of forage:concentrate of 75:25, 55:45, and 35:65. Corn silage and hay crop silage were combined in a ratio of 2:1 (dry basis) in each case, and diets were offered for ad libitum intake as complete feeds for an 11-wk experimental period plus 2 wk for a digestion trial. In regression analysis as energy density increased, feed intake, milk yield, milk protein, and lactose yields increased linearly, urea nitrogen in blood plasma decreased linearly, and milk fat percent and yield decreased curvilinearly. As dietary protein increased, feed intake, fat-corrected milk, milk fat yield, and plasma urea nitrogen increased linearly, and yields of milk, solids-corrected milk, milk protein, and lactose increased curvilinearly. Actual milk yield adjusted for dry matter intake increased with greater energy density but not with higher protein concentration. Increases of energy and protein each resulted in linear increases of digestibility of dry matter, crude protein, and energy of diets. There were no interactions of energy X protein for these measurements. Cows in first lactation will increase milk production in response to increasing protein over a range of energy densities when feed intake is increased.


Polyhydroxylated steroidal glycosides from Paris polyphylla.
Three new steroidal saponins, parisyunnanosides G-I (1-3), one new C(21) steroidal glycoside, parisyunnanoside J (4), and three known compounds, padelaoside B (5), pinnatasterone (6), and 20-hydroxyecdyson (7), were isolated from the rhizomes of Paris polyphylla Smith var. yunnanensis. Compounds 1 and 3 have unique trisdesmoside structures that include a C-21 β-d-galactopyranose moiety. All compounds were evaluated for their cytotoxicity against human CCRF leukemia cells.


Utilizing Percutaneous Cholecystostomy Tube as a Temporary Minimally Invasive Approach for Acute Cholecystitis during Third Trimester of a High-Risk Pregnancy.
Laparoscopic cholecystectomy (LC) is the treatment modality of choice for symptomatic cholelithiasis and cholecystitis during pregnancy and is associated with shorter length of stay, shorter operative times, and fewer complications compared to open cholecystectomy. However, in high-risk pregnant patients, LC can be challenging. Percutaneous cholecystostomy tube (PCT) offers a temporary management option during the peripartum period until interval LC is performed. We present a case of a high-risk pregnancy involving a 41-year-old woman at the 34th week of gestation with a dichorionic-diamniotic-twin gestation with signs and symptoms of acute cholecystitis. Given the patient's high-risk status, a less intensive intervention, PCT, was performed for gallbladder decompression. An interval LC was performed on postpartum day 4 after caesarean section. Current surgical guidelines suggest that laparoscopy can be safely used to treat biliary disease during pregnancy in all trimesters. Although rarely used as a first-line intervention for gallbladder disease, PCT is an important minimally invasive procedure for treatment of cholecystitis in patients who are poor surgical candidates. Our case is unique due to the twin gestation, advanced maternal age, and gestational age.


Cutaneous blood flow rate in areas with and without arteriovenous anastomoses during exercise.
In 10 healthy subjects, skin blood flow rate was measured in the thumb pulp by the heat-washout method, and in the skin fold between the thumb and the forefinger by the 133Xe-washout method. The former but not the latter skin area contains arteriovenous anastomoses (AVAs). In response to 10 min moderate bicycle exercise, an instantaneous decrease in flow was seen in the thumb pulp followed after about 4.6 min by an increase to resting levels. Blood flow in the skin fold remained constant. The results indicate that the initial reduction in blood flow rate and later increase observed in the finger at the onset of moderate exercise take place in the AVAs and not in the capillaries.


DIFFERENTIATION OF A MULTIGENE FAMILY BETWEEN POPULATIONS.
Differentiation of a multigene family between populations is investigated under the forces of intrachromosomal unbiased gene conversion, neutral mutation, recombination, and random drift. The infinite-site model without recombination within the gene is employed, and the average numbers of the different sites between pairs of genes at the same locus and at different loci from two populations that divided some time ago are calculated as functions of time. Since differentiation is a relative concept in which differences between populations are expressed in comparison with those within a population and since there is most likely a reduction in population size after the division of populations, the time-dependent behavior of the corresponding quantities within a population is also investigated using approximate and numerical methods. It is found that intrachromosomal unbiased gene conversion promotes differentiation at the same locus but promotes or retards that between different loci, depending on the parameters in a recently divided population.


A Pipeline for Predicting the Treatment Response of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer Using Single MRI Modality: Combining Deep Segmentation Network and Radiomics Analysis Based on "Suspicious Region".
Patients with locally advanced rectal cancer (LARC) who achieve a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) typically have a good prognosis. An early and accurate prediction of the treatment response, i.e., whether a patient achieves pCR, could significantly help doctors make tailored plans for LARC patients. This study proposes a pipeline of pCR prediction using a combination of deep learning and radiomics analysis. Taking into consideration missing pre-nCRT magnetic resonance imaging (MRI), as well as aiming to improve the efficiency for clinical application, the pipeline only included a post-nCRT T2-weighted (T2-w) MRI. Unlike other studies that attempted to carefully find the region of interest (ROI) using a pre-nCRT MRI as a reference, we placed the ROI on a "suspicious region", which is a continuous area that has a high possibility to contain a tumor or fibrosis as assessed by radiologists. A deep segmentation network, termed the two-stage rectum-aware U-Net (tsraU-Net), is designed to segment the ROI to substitute for a time-consuming manual delineation. This is followed by a radiomics analysis model based on the ROI to extract the hidden information and predict the pCR status. The data from a total of 275 patients were collected from two hospitals and partitioned into four datasets: Seg-T (N = 88) for training the tsraUNet, Rad-T (N = 107) for building the radiomics model, In-V (N = 46) for internal validation, and Ex-V (N = 34) for external validation. The proposed method achieved an area under the curve (AUC) of 0.829 (95% confidence interval [CI]: 0.821, 0.837) on In-V and 0.815 (95% CI, 0.801, 0.830) on Ex-V. The performance of the method was considerable and stable in two validation sets, indicating that the well-designed pipeline has the potential to be used in real clinical procedures.


Differences in respiratory muscle activity during cycling and walking do not influence dyspnea perception in obese patients with COPD.
In patients with combined obesity and chronic obstructive pulmonary disease (COPD), dyspnea intensity at matched work rates during weight-supported cycling and weight-bearing walking is similar, despite consistent metabolic differences between test modalities. The present study examined the influence of differences in activity of the diaphragm and abdominal muscles during cycling and walking on intensity and quality of dyspnea at matched ventilation in obese patients with COPD. We compared respiratory muscle activity patterns and dyspnea ratings during incremental cycle and treadmill exercise tests, where work rate was matched, in 12 obese (body mass index 36.6 ± 5.4 kg/m(2); mean ± SD) patients with moderate COPD. We used a multipair electrode-balloon catheter to compare electromyography of the diaphragm and esophageal, gastric, and transdiaphragmatic pressures during the two exercise tests. Ventilation, breathing pattern, operating lung volumes, global respiratory effort, and electrical activation of the diaphragm were similar across exercise modalities for a given work rate. The cycling position was associated with greater neuromuscular efficiency of the diaphragm (P < 0.01), greater diaphragm use (P < 0.01) measured by the ventilatory muscle recruitment index, and less expiratory muscle activity compared (P < 0.01) with treadmill walking. However, intensity and quality of dyspnea were similar between exercise modalities. In obese patients with COPD, altered respiratory muscle activity due to body position differences between cycling and walking did not modulate perceived dyspnea when indirect measures of respiratory neural drive were unchanged.


Point prevalence of healthcare-associated infections and antibiotic use in a tertiary care teaching hospital in Nepal: A cross-sectional study.
Information on the burden of healthcare-associated infections (HAIs) and patterns of antibiotic use are prerequisites for infection prevention and control (IPC) and antibiotics stewardship programmes. However, a few studies have been reported from resource-limited settings and many of them have not used standard definitions to diagnose HAI precluding benchmarking with regional or international data. This study aims to estimate the prevalence of HAIs and antibiotic use in our centre. We conducted a point prevalence survey in a 350-bed university hospital in Kathmandu, Nepal in April 2019. We reviewed all patients aged ⩾ 18 years admitted to the hospital for at least two calendar days and evaluated for the three common HAIs-pneumonia, urinary tract infection and surgical site infection. We used the clinical criteria by the European Center for Disease Prevention and Control to diagnose the HAIs. We also collected information on the antibiotics used. Of 160 eligible patients, 18 (11.25%) had HAIs and 114 (87.5%) were on antibiotics, with more than half of them (61/114 patients, 53.5%) receiving two or more antibiotics. This highlights the need for effective implementation of IPC as well as antibiotics stewardship programmes in our centre.


Photoreceptive oscillators within neurons of the premammillary nucleus (PMM) and seasonal reproduction in temperate zone birds.
The pathway for light transmission regulating the reproductive neuroendocrine system in temperate zone birds remains elusive. Based on the evidence provided from our studies with female turkeys, it is suggested that the circadian clock regulating reproductive seasonality is located in putatively photosensitive dopamine-melatonin (DA-MEL) neurons residing in the premammillary nucleus (PMM) of the caudal hypothalamus. Melanopsin is expressed by these neurons; a known photopigment which mediates light information pertaining to the entrainment of the clock. Exposure to a gonad stimulatory photoperiod enhances the activity of the DAergic system within DA-MEL neurons. DAergic activity encoding the light information is transmitted to the pars tuberalis, where thyroid-stimulating hormone, beta (TSHβ) cells reside, and induces the release of TSH. TSH stimulates tanycytes lining the base of the third ventricle and activates type 2 deiodinase in the ependymal which enhances triiodothyronine (T3) synthesis. T3 facilitates the release of gonadotropin-releasing hormone-I which stimulates luteinizing hormone/follicle stimulating hormone release and gonad recrudescence. These data taken together with the findings that clock genes are rhythmically expressed in the PMM where DA-MEL neurons are localized imply that endogenous oscillators containing photoreceptors within DA-MEL neurons are important in regulating the DA and MEL rhythms that drive the circadian cycle controlling seasonal reproduction.


Access to confidential sexual health services.
The authors conducted one-on-one interviews with adolescent females, aged 13 to 16, concerning their perception of the confidentiality of sexual health services available to them. Participants were selected from an urban school with a youth health centre (YHC) and also from a rural school without access to a YHC. They typically viewed traditional health services as not confidential and reported concern about disclosure to parents. This qualitative study suggests that adolescent females have an absolute need to maintain positive parental regard by preventing disclosure of sexual activity.


Photolabile antibiotics as probes of ribosomal structure and function.
In summary, our studies have resulted in the development of new reagents and synthetic procedures for the introduction of both radioactivity and photolability into antibiotics; have provided examples of how PAGE analysis can be used to conveniently test various aspects of photoaffinity labeling of complex receptors, such as the ribosome; have revealed examples of unexpected photoreactivity, as in the case of puromycin; and have provided strong evidence regarding the three-dimensional location of the peptidyl transferase center and the site of that interaction of the 3' and of aminoacyl-tRNA with the 30S subunit. Work that is now in progress should provide similar detailed information regarding other functional sites in the ribosome.


Peyer's Patches as a Portal for DNA Delivery by Lactococcus lactis in Vivo.
Application of food-grade Lactococcus lactis (L. lactis) as a safe delivery tool for DNA vaccines and therapeutic proteins has been well investigated. Although some studies showed that eukaryotic expression plasmids were transferred from L. lactis to enterocytes, the precise mechanism of the DNA transfer remains unknown. In this study, we generated an invasive L. lactis strain that expresses "murinized" Internalin A, an invasin of intracellular bacteria Listeria monocytogenes with two amino acid alterations for invasion into murine cells, and confirmed that this L. lactis strain delivered DNA in an invasin-dependent manner into a monolayer of epithelial cells polarized to mimic the gastrointestinal tract environment. Although invasive L. lactis inoculated orally can deliver DNA into enterocytes in the gastrointestinal tract of mice, the efficiency of DNA transfer was similar to that of non-invasive L. lactis strain, suggesting that the in vivo DNA transfer from L. lactis occurs invasin-independently. A ligated-intestinal loop assay, a method for a short-term culturing of the whole intestine filled with materials to evaluate the interaction of the materials with intestinal cells, demonstrated that both non-invasive and invasive L. lactis strains were present in the Peyer's patches of the small intestine. On the other hand, few L. lactis was detected in the non-Peyer's patch epithelial region. Thus, our observations lead us to speculate that DNA transfer from L. lactis occurs predominantly in the Peyer's patches in an invasin-independent manner.


[Autism, epilepsy and tuberous sclerosis complex: a functional model linked to mTOR pathway].
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. Brain disorders are the origin of more frequent and severe problems and include infantile spasms, intractable epilepsy, brain tumors, cognitive disabilities, and autism. TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. AIM. To review the etiopathogenic mechanisms and the natural course of the association of autism and epilepsy in TSC. Both the clinical and the neuroimaging findings of TSC, including early onset epilepsy and the localization of cortical tubers in the temporal lobes, and the molecular understanding of the mTOR signaling pathway, not only involved in cell growth, but also in synaptogenesis, synaptic plasticity and neuronal functioning, have suggested a multimodal origin of autism in these patients. A greater understanding of the pathogenetic mechanisms underlying autism in TSC could help in devising targeted and potentially more effective treatment strategies. Antagonism of the mTOR pathway with rapamycin and everolimus may provide new therapeutic options for these TSC patients.


Cardiac angiosarcoma: an unexpected diagnosis.
Cardiac angiosarcoma is a rare entity. The incidence through autopsy findings ranges between 0.001% and 0.03%. The disease usually presents with non-specific symptoms, although asymptomatic cases are frequent; therefore, diagnosis is unexpected and consequently delayed. The authors report the case of a middle-aged man with a recent onset cough and dyspnea. He sought medical care several times without receiving a definite diagnosis until a plain chest radiography was taken showing a mediastinal enlargement, which was the reason why he was hospitalized for clinical investigation. During the diagnostic workup, an echodopplercardiogram and a thoracic computed tomography were performed, showing a heterogeneous soft-tissue mass infiltrating the pericardium and the anterior atrial wall. Multiple and scattered pulmonary nodules were also present. A pulmonary nodule was biopsied, which revealed an angiosarcoma. The clinical features added to the radiological and histological findings permitted the diagnosis of right atrial angiosarcoma. The authors highlight the unexpected pattern in the presentation of cardiac tumors.


Bird-Window Collisions: A Critical Animal Welfare and Conservation Issue.
Sheet glass and plastic in the form of clear and reflective windows are universally lethal to birds. Reasonable interpretation of available scientific evidence describes windows as a principal human-associated avian mortality factor that is an indiscriminant killer of common species as well as species of conservation concern. A conservative toll estimates 1 billion or more annual fatalities in the United States alone. The injury and death from birds striking windows are foreseeable and preventable, but the most promising legal measures and commercial products are not being applied or made available to protect defenseless victims. Avian window casualties are important for birds and people, and they have nonhuman animal welfare, biodiversity, sustainability, legal, and ethical and moral value justifying responsible human action. Preventing this unintended and unwanted lethal hazard for free-flying birds should be an obligation. Short-term solutions include retrofitting existing panes with a variety of proven measures that among others include applying various materials to cover the outside surface of windows. Long-term solutions include current and proposed bird-safe sheet glass and plastic for remodeling and new construction that have patterns that transform windows into barriers that birds see and avoid.


Enzyme induction by phenobarbitone and vitamin K1 disposition in man.
The plasma disposition of an intravenous pharmacological dose of vitamin K1 was determined in seven healthy volunteers before and after chronic administration of phenobarbitone (100 mg nocte). Phenobarbitone produced a significant increase in antipyrine clearance and 6 beta-hydroxycortisol excretion in all volunteers, indicating induction of hepatic microsomal mixed-function oxidase enzymes. However, phenobarbitone administration had no effect on the plasma disposition of vitamin K1. We conclude therefore, that vitamin K1 is not metabolized to any significant extent, by phenobarbitone-inducible mixed-function oxidase enzymes.


The value of serum myoglobin determinations in the early diagnosis of acute myocardial infarction.
Myoglobin has been measured in sera from 305 consecutive patients with suspected acute myocardial infarction (AMI) to study the clinical value in relation to other diagnostic methods. On admission the frequency of false negative (i.e. the diagnostic sensitivity) myoglobin values was 28% in the AMI group as compared with 60% for serum creatine kinase (CK) and 46% for serum aspartate aminotransferase (ASAT). Four hours after admission the corresponding figures were 2, 31 and 29%. This makes the diagnostic sensitivity of the myoglobin test 0.98, which is significantly higher (p less than 0.001) than that of the two enzyme tests. The predictive value of a negative myoglobin test was 0.97 and also significantly higher (p less than 0.001 and p less than 0.01) than for CK and ASAT. S-myoglobin was further related to the number of complications and the prognosis of the patients, and high levels appeared to be an unfavourable sign, particularly in combination with an anterior wall infarct. This study has demonstrated and confirmed the superior diagnostic sensitivity of myoglobin determination in early AMI. The inclusion of S-myoglobin in the routine diagnosis of AMI warrants serious consideration.


Performance of the VUV beamline 4.1 at the SRS, Daresbury Laboratory.
The performance of a recently commissioned beamline, designated BL4.1, at the SRS, Daresbury Laboratory, is described. This beamline covers the energy range 15 >/= hupsilon >/= 200 eV, using a spherical grating monochromator, and is equipped with a UHV surface-science endstation containing a Scienta SES200 and an HA54 angle-resolving electron-energy analyser. Design parameters and optical specifications are tabulated. Monochromator resolution has been determined by measuring the Fermi edge of a Pt foil cooled to 40 K and these values are compared with the calculated resolution. The flux delivered to the endstation has been measured directly using a calibrated photodiode. The performance of the beamline is further illustrated by reference to a study of the angular distribution of photoemitted intensity from a band-gap state on a TiO(2)(110) 1 x 2 surface.


Artemether-lumefantrine treatment failure of uncomplicated Plasmodium falciparum malaria in travellers coming from Angola and Mozambique.
The failure of artemisinin combination therapy (ACT) in malaria patients returning from endemic regions may be driven by parasite resistance to this treatment. ACT is used globally as the first-line treatment for Plasmodium falciparum malaria. However, artemisinin-resistant strains of P. falciparum have emerged and spread across Southeast Asia, with the risk of reaching high malaria burden regions in Africa and elsewhere. Here, we report on two malaria imported cases from Africa with possible parasite resistance to the ACT artemether-lumefantrine (AL). Case presentation: Two middle-aged males returning from Angola and Mozambique developed malaria symptoms in Portugal, where they were diagnosed and received treatment with AL as hospital inpatients. After apparent cure and discharge from hospital, these individuals returned to hospital showing signs of late clinical failure. Molecular analysis was performed across a number of drug resistance associated genes. No evidence of pfk13-mediated artemisinin resistance was found. Both subjects had complete parasite clearance after treatment with non-ACT antimalarials. Conclusion: Our case-studies highlights the need for close monitoring of signs of unsatisfactory antimalarial efficacy among AL treated patients and the possible implication of other genes or mutations in the parasite response to ACTs.


Therapeutic dilemma of disseminated CNS germinoma and the potential of increased platinum-based chemotherapy delivery with osmotic blood-brain barrier disruption.
In contrast to disseminated extraneural germinoma, systemic chemotherapy in disseminated central nervous system germinoma often results in only transient responses. After surgery, cytoreduction was accomplished with systemic multiagent platinum-based chemotherapy in 4 consecutive patients known to have a poor prognosis, due to central nervous system germinoma at more than one anatomic site. When tumor enhancement resolved (i.e., blood-brain barrier integrity was restored), intensive consolidation therapy with carboplatin and etoposide was given in association with mannitol-induced osmotic blood-brain barrier disruption. Complete responses occurred in all 4 patients and currently 3 are tumor-free without radiotherapy 24-40 months from diagnosis, suggesting the importance of increased drug delivery for an extended period.


Morphological and atomic analytical changes of root canal wall dentin after treatment with thirty-eight percent Ag(NH3)2F solution and CO2 laser.
The morphological and atomic analytical changes of the root canal wall dentin, treated with 38% diamine silver fluoride [Ag(NH3)2F] solution and irradiated by carbon dioxide (CO2) laser at the continuous wave mode were evaluated in vitro. There has been no report on the morphological or atomic analytical changes of the effect of Ag(NH3)2F solution and CO2 laser on root canal walls. Eighty extracted human single-rooted teeth were instrumented using a conventional technique and randomly divided into 8 groups of 10 teeth each. The teeth in group 1 were neither treated with Ag(NH3)2F solution nor lased. Groups 2, 3, and 4 were irradiated by laser at the parameters of 1, 2, and 3 W for 10 seconds, respectively. Group 5 was treated with Ag(NH3)2F solution only. The other 3 groups were treated with Ag(NH3)2F solution and then lased by the same method as groups 2, 3, and 4. After this treatment, 4 specimens each from group 1, 5, and 6 were analyzed by scanning electron microscope-energy dispersive x-ray spectroscopy (SEM-EDX) and other specimens in all groups were examined by scanning electron microscopy (SEM). The smear layer and debris of the control and lased specimens were not completely removed, but the areas of carbonization of evaporation of smear layer and open dentinal tubules were observed on the specimens treated with Ag(NH3)2F and lased at 1 W (group 6). After laser irradiation, the amount of silver on the root canal surfaces was significantly reduced to approximately one-third level on the measurement of SEM-EDX (p < 0.01). These results suggest that CO2 laser is an effective method to remove or melt smear layer of root canal walls after treatment with 38% Ag(NH3)2F solution if an appropriate parameter is selected.


[Dynamics of penetration of "solid" nanoconstructions based on double-stranded DNA complexed with gadolinium into CHO cells].
Currently, neutron capture therapy is a promising cancer treatment. This method is based on the reaction of the thermal neutron capture by some non-radioactive elements (e.g., Gds57), which results in subsequent emission of electrons and gamma rays. An effective instrument for delivery of gadolinium into the tumor tissue are the particles of the "rigid" nanostructures (NS) based on double-stranded DNA complexes with gadolinium (NS-Gd). The local concentration of Gd in such nanostructures may reach 40%. To optimize the process of neutron capture therapy it is very important to investigate possible penetration mechanisms of NS-Gd particles into the tumor cells. In this work, the dynamics of interaction NS-Gd with cultivated chinese hamster ovary cells (CHO) was studied by confocal and electron microscopy. It is shown that NS-Gd are able to enter CHO cells. This process begins in about 1 hour after the start ofincubation. After 6 h NS-Gd particles were detected in almost all cells. A further increase of the incubation time does not lead to significant changes in cell morphology, although the number NS-Gd inside the cells increases. The plasma membrane of the cells remains intact. The NS-Gd particles, which entered the cells, remain inside the cells for a long time. The data obtained show that NS-Gd are relatively low-toxic and suggest that the presence of NS-Gd in the tumor cells does not prevent their division. The data obtained are important for improving the efficiency of the neutron capture therapy method.


A-single spermatogonia heterogeneity and cell cycles synchronize with rat seminiferous epithelium stages VIII-IX.
In mammalian testes, "A-single" spermatogonia function as stem cells that sustain sperm production for fertilizing eggs. Yet, it is not understood how cellular niches regulate the developmental fate of A-single spermatogonia. Here, immunolabeling studies in rat testes define a novel population of ERBB3(+) germ cells as approximately 5% of total SNAP91(+) A-single spermatogonia along a spermatogenic wave. As a function of time, ERBB3(+) A-single spermatogonia are detected during a 1- to 2-day period each 12.9-day sperm cycle, representing 35%-40% of SNAP91(+) A-single spermatogonia in stages VIII-IX of the seminiferous epithelium. Local concentrations of ERBB3(+) A-single spermatogonia are maintained under the mean density measured for neighboring SNAP91(+) A-single spermatogonia, potentially indicative of niche saturation. ERBB3(+) spermatogonia also synchronize their cell cycles with epithelium stages VIII-IX, where they form physical associations with preleptotene spermatocytes transiting the blood-testis barrier and Sertoli cells undergoing sperm release. Thus, A-single spermatogonia heterogeneity within this short-lived and reoccurring microenvironment invokes novel theories on how cellular niches integrate with testicular physiology to orchestrate sperm development in mammals.


The effect of environmental pH and fluoride from the substratum on the development of biofilms of selected oral bacteria.
The present study was initiated to answer the question, "Does fluoride from the substratum influence the accumulation of bacterial cells in an associated biofilm?" 'Fluoride-bound hydroxyapatite' (FHA) and 'fluoride-free hydroxyapatite' (HA) rods were prepared as test and control surfaces, respectively. Biofilms of S. mutans BM71, A. naeslundii genospecies 2 WVU627, and L. casei BM225 accumulated on the surfaces of rods in a semi-defined, mucin-based medium in a chemostat. Culture conditions were varied from pH 4.5 to 7.0 under carbon (glucose) limitation and excess, at a dilution rate of D = 0.1 h-1. Low environmental pH reduced both the numbers of cells on HA surfaces during the early phases (from 0 to 2 h) of accumulation and the final numbers of cells in mature biofilms (20 h). The initial adherence of cells was unaffected by surface fluoride under any of the conditions tested. Similarly, biofilm cells under carbon limitation and those under carbon excess at pH 7.0 were not affected by surface fluoride. However, at low environmental pH values, pH 5.5 for S. mutans and pH 6.0 for A. naeslundii under glucose excess, the accumulation of biofilm cells on the FHA surfaces was significantly reduced (p < 0.05-0.001). Biofilm cell number doubling times of S. mutans and A. naeslundii were increased on FHA relative to HA. Biofilms of L. casei were not significantly affected, even at pH 4.5 in glucose excess. The results confirmed that fluoride from the substratum affected fluoride-sensitive biofilm cells but only under conditions of glucose excess ad low pH.


Sacral neuromodulation for female pelvic floor disorders.
Objective: To systematically review available studies on the effectiveness and safety of sacral neuromodulation (SNM) in women with various pelvic floor disorders not responding to more conservative treatment, as SNM is indicated in such women. Methods: Data source: We did a systematic review through the PubMed and the Cochrane Library according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement from 1998 to 2018 in English using the keywords 'Sacral Neuromodulation' and 'Sacral Nerve Stimulation'. Study selection: Randomised controlled trials and prospective studies were selected, with a minimum sample size of 20 patients and ≥6 months of follow-up. Results: We identified 19 articles. A ≥50% reduction in symptoms qualifies the patient for a permanent implant. Several advances have been introduced into SNM to decrease the invasiveness of the procedure, including a smaller implantable pulse generator battery (improved comfort) and better localisation of the lead wire (improved outcome). The literature reports success for overactive bladder (OAB) to range between 56% and 68% (up to 80%). We report a 5-year therapeutic success rate of 67%. In our previous studies, 38% of our patients with urge urinary incontinence achieved complete continence at 60-months follow-up, with a therapeutic response rate of 57%. Effectiveness in patients with urinary retention and faecal incontinence are about 70% and 85%, respectively. Effectiveness in interstitial cystitis/bladder pain syndrome appears to be lower compared with OAB. Conclusion: SNM is a safe and effective therapy for women with various pelvic floor disorders. Abbreviations: BONT: botulinum toxin; FDA: USA Food and Drug Administration; FS: Fowler's syndrome; FI: faecal incontinence; IC/BPS: interstitial cystitis/bladder pain syndrome; ICIQ-OABqol: International Consultation on Incontinence Modular Questionnaire-Overactive Bladder Symptoms Quality of Life; INS: implantable neurostimulator; OAB: overactive bladder; PET: positron emission tomography; PNE: peripheral nerve evaluation; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PTNM: posterior tibial nerve modulation; PVR: post-void residual urine; QoL: quality of life; RCT: randomised controlled trial; SNM: sacral neuromodulation; (U)UI: (urgency) urinary incontinence.


Body weight and self-control in the United States and Britain since the 1950s.
Body weight has risen in defiance of health and appearance norms. This is framed in terms of the problem of time-inconsistency and self-control. The social epidemics of overeating and slimming were driven by market forces and the psychology of eating: restrained eating was easily disinhibited by the stresses of new rewards. For men, the rise in body weight was associated with the decline of family eating and exposure to greater food variety. For women, the 'cult of slimming' was associated with mating and workplace competition, driven initially by adverse sex ratios. Food abundance made it difficult for rational consumers to conform with social norms.


End of life care in the ICU: current practice and future hopes.
Dying well in the United States is not the standard of care, particularly in critical care units. A number of factors contribute to this clinical deficiency, yet opportunities and strategies to correct the deficiencies are evident through the work of end-of-life advocates and clinical pioneers in nursing and medicine. The purpose of this paper is to describe barriers to optimal end of life care in the ICU and to recommend strategies for making improvements. Ideally, all persons who are not expected to survive a critical illness will experience compassionate, comprehensive, patient and family-focused attention directed at allowing the patient to die well.


Home monitoring for lung transplant candidates.
Home monitoring by lung transplant recipients has been effective for early detection of clinical problems. This study used an electronic diary for home monitoring by lung transplant candidates to improve communication between candidates and the transplant team. Candidates were randomized into control (52 subjects following standard telephone reporting procedures) and intervention (67 subjects using an electronic diary to record and transmit a range of health-related measures) groups. Outcome measures were monitoring adherence and level of communication (for monitor acceptability and utilization), hospital length of stay after transplantation and survival at 4 months (for clinical effectiveness). Subjects used the diary without difficulty and with good adherence. Subjects and coordinator contacts were similar between groups; intervention group subjects were positive regarding contact based on diary use. There were no significant differences in clinical outcomes between groups. Changing diary questions might improve the effectiveness of electronic monitoring for lung transplant candidates.


Me, us, or them: who is more conformist? Perception of conformity and political orientation.
Research has shown that people perceive others as more vulnerable than themselves to media communication, and their political out-group as more vulnerable than their political in-group. In the present study, the authors predicted that the same two biases would appear with respect to another kind of influence--conformity--but that participants' judgments would display a different pattern according to their political orientations. Right-wing and left-wing university students were asked to evaluate conformity and to estimate how conformist they, their political in-group, their political out-group, and other groups are. As hypothesized, right-wingers expressed more ambivalence toward conformity and viewed it less negatively than did left-wingers. Political orientation had no impact on the discrepancy between self and others, but it did moderate the in-group-out-group discrepancy.


Mini-review: Brazilian fungi diversity for biomass degradation.
Brazil houses over 10% of the total number of known species on Earth, with a great diversity of plants and fungi. The collection, isolation, identification and conservation of filamentous fungi with relevance to agriculture, pharmaceutical, food and biotechnological industries in Biological Resource Centers (CRBs) is very important to the development of a nation's scientific and technological infrastructure. In Brazil, 36 fungal collections are registered in the database of International Collections. Several federal and state programs have encouraged the formation of a researcher's network in order to study natural resources and the nation's biodiversity. In this context, Brazilian researchers have been on the frontiers of knowledge, investigating the enzymatic systems from native filamentous fungi with potential for biomass degradation and biotechnological application. In this review, we address recent progress in Brazilian fungal research, focusing on the identification and study of fungi and enzymes with potential for biomass degradation and application in bioenergy.


SLCO1B3 and SLCO2B1 Genotypes, Androgen Deprivation Therapy, and Prostate Cancer Outcomes: A Prospective Cohort Study and Meta-analysis.
Solute carrier organic anion (SLCO) transporters (OATP transporters) are involved in cellular uptake of drugs and hormones. Germline variants in SLCO1B3 and SLCO2B1 have been implicated in prostate cancer progression and therapy response, including to androgen deprivation and statin medications, but results have appeared heterogeneous. We conducted a cohort study of five single-nucleotide polymorphisms (SNPs) in SLCO1B3 and SLCO2B1 with prior evidence among 3,208 men with prostate cancer who participated in the Health Professionals Follow-up Study or the Physicians' Health Study, following participants prospectively after diagnosis over 32 years (median, 14 years) for development of metastases and cancer-specific death (lethal disease, 382 events). Results were suggestive of, but not conclusive for, associations between some SNPs and lethal disease and differences by androgen deprivation and statin use. All candidate SNPs were associated with SLCO mRNA expression in tumor-adjacent prostate tissue. We also conducted a systematic review and harmonized estimates for a dose-response meta-analysis of all available data, including 9 further studies, for a total of 5,598 patients and 1473 clinical events. The A allele of the exonic SNP rs12422149 (14% prevalence), which leads to lower cellular testosterone precursor uptake via SLCO2B1, was associated with lower rates of prostate cancer progression (hazard ratio per A allele, 0.80; 95% confidence interval, 0.69 to 0.93), with little heterogeneity between studies (I2, 0.27). Collectively, the totality of evidence suggests a strong association between inherited genetic variation in SLCO2B1 and prostate cancer prognosis, with potential clinical use in risk stratification related to androgen deprivation therapy.


Identifying candidate oocyte reprogramming factors using cross-species global transcriptional analysis.
There is mounting evidence to suggest that the epigenetic reprogramming capacity of the oocyte is superior to that of the current factor-based reprogramming approaches and that some factor-reprogrammed induced pluripotent stem cells (iPSCs) retain a degree of epigenetic memory that can influence differentiation capacity and may be linked to the observed expression of immunogenicity genes in iPSC derivatives. One hypothesis for this differential reprogramming capacity is the "chromatin loosening/enhanced reprogramming" concept, as previously described by John Gurdon and Ian Wilmut, as well as others, which postulates that the oocyte possesses factors that loosen the somatic cell chromatin structure, providing the epigenetic and transcriptional regulatory factors more ready access to repressed genes and thereby significantly increasing epigenetic reprogramming. However, to empirically test this hypothesis a list of candidate oocyte reprogramming factors (CORFs) must be ascertained that are significantly expressed in metaphase II oocytes. Previous studies have focused on intraspecies or cross-species transcriptional analysis of up to two different species of oocytes. In this study, we have identified eight CORFs (ARID2, ASF1A, ASF1B, DPPA3, ING3, MSL3, H1FOO, and KDM6B) based on unbiased global transcriptional analysis of oocytes from three different species (human, rhesus monkey, and mouse) that both demonstrate significant (p<0.05, FC>3) expression in oocytes of all three species and have well-established roles in loosening/opening up chromatin structure. We also identified an additional 15 CORFs that fit within our proposed "chromatin opening/fate transformative" (COFT) model. These CORFs may be able to augment Shinya Yamanaka's previously identified reprogramming factors (OCT4, SOX2, KLF4, and cMYC) and potentially facilitate the removal of epigenetic memory in iPSCs and/or reduce the expression of immunogenicity genes in iPSC derivatives, and may have applications in future personalized pluripotent stem cell based therapeutics.


Meta-analysis of the relationship between methylenetetrahydrofolate reductase C677T and A1298C polymorphism and venous thromboembolism in the Caucasian and Asian.
Recent years, it is a highly debated topic that whether methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and A1298C polymorphism could increase susceptibility to venous thromboembolism (VTE) in the Asian and Caucasian. Therefore, we expect to settle that controversy evidentially. Basic methods: Electronic databases (Pubmed, embase, Cochrane library, scopus, OvidSP, Wiley Online library, Springer link, EBSCO, Elsevier Science Direct, Google scholar) without date limitation were searched. Crude odds ratio (OR) along with 95% confidence interval (95% CI) was calculated to assess the association quantitatively. Finally, a total of 37 eligible studies were included, containing 31 for MTHFR C677T polymorphism and 6 for MTHFR A1298C polymorphism. The pooled results suggested that MTHFR C677T mutation may increase susceptibility to VTE in reverse recessive model (CC+CT vs TT): OR = 0.68 (0.56, 0.83), reverse dominant model (CC vs CT +TT): OR = 0.82 (0.72, 0.94), heterozygote model (CT vs TT): OR = 0.65 (0.52, 0.81), homozygote model (CC vs TT): OR = 0.73 (0.60, 0.89) and allele model (C vs T): OR = 0.80 (0.71, 0.90). Subgroup analysis about Asian also support that results, but Caucasian group not. In addition, MTHFR A1298C polymorphism may be not related to VTE in all genetic model. The results of meta-analysis indicated that MTHFR C677T polymorphism might increase the risk of VTE, especially in Asian population.


New developments in treatment planning and verification of particle beam therapy.
Charged particle beam therapy has been used for almost 60 years. During the initial 40 years, the medical use of protons and heavy ions was explored at accelerator laboratories in a limited number of patients and for a limited number of cancerous and non-cancerous disease conditions. After the development of computed tomography and 3D treatment planning, it was time to move charged particle therapy into the clinical realm. This happened in October 1991 when an ocular melanoma patient became the first patient to be treated at Loma Linda University Medical Center in California. Due to the increased awareness of the advantages of charged particle therapy and promising results of single-institution experiences, one currently observes a phase of rapid expansion of proton treatment centers throughout the world. A few of these centers are combined proton/carbon ion facilities. It is very important that the technological evolution of charged particle therapy will continue during this phase of clinical expansion to ensure that the increasing number of patients exposed to therapeutic charged particles will benefit most from the advantageous dose distributions that these particles afford. This report will give an overview of translational research activities related to planning and verification of proton therapy in which the authors have been involved for a number of years. While our activities focus on protons, these developments are to a large degree also applicable to carbon ion therapy.


[EGFR-ERK signaling pathway down-regulates miRNA-145 in lung cancer cells].
To investigate the relationship between EGFR activation and down-regulation of miRNA-145 in lung cancer. Normal human lung epithelia cell line (BEAS-2B), human lung adenocarcinoma cell lines with wild-type EGFR (A549 and H292) and human lung adenocarcinoma cell lines with EGFR mutation (H1975 and H1650) were chosen in this study. The levels of miRNA-145 and p-EGFR were determined by quantitative real-time PCR (qRT-PCR) and Western blotting, respectively, and the relationship between p-EGFR and miRNA-145 levels was analyzed. The miRNA-145 levels were determined by qRT-PCR after activating EGFR with EGF or blocking EGFR signal pathway with AG1478. In addition, ERK1/2 inhibitor U0126 was used to inhibit ERK1/2 activation and then the expression of miRNA-145 was detected. The miRNA-145 levels were closely negatively related with p-EGFR in lung cancer cells (r = -0.926, P = 0.024). EGF down-regulated miRNA-145 expression, particularly in BEAS-2B cells (53.0%; t = 30.993, P = 0.001) and A549 cells (42.6%; t = 14.326, P = 0.005).The miRNA-145 was up-regulated after inhibiting p-EGFR with AG1478, and significantly enhanced by 67.5% in H1975 cells when treated with AG1478 (t = 8.269, P = 0.014). The ERK1/2 signal pathway was activated by p-EGFR. U0126 restored the miRNA-145 down-regulation induced by EGFR-activation in lung cancer cells. The activation of EGFR down-regulates miRNA-145 expression through ERK1/2 in lung cancer cells.


Quantitative model for near-field scanning microwave microscopy: application to metrology of thin film dielectrics.
We have experimentally verified a recently proposed theoretical model for near-field microwave microscopy of multilayer media. The model addresses a near-field microwave probe as an electrically small antenna with a Gaussian-like current distribution that has a single characteristic length scale on the order of the probe size. Electrodynamic response of an antenna is calculated using Green functions in the form of integral transforms for electric and magnetic fields (both quasistatic and propagating), which are generated by a pointlike dipole. Experimental data were obtained at 4 GHz using a near-field scanning microwave microscope with aperture size of approximately 5 microm for a set of six SiO(2) films with thickness ranging from 0.1 to 1.5 microm. For each sample the probe resonant frequency was both measured and simulated as a function of the tip-sample distance, and good agreement between the theory and experimental data was observed. It was found that the model is capable of determining thin film dielectric constant with accuracy of approximately 5%-7%.


Comparison of four channelled videolaryngoscopes to Macintosh laryngoscope for simulated intubation of critically ill patients: the randomized MACMAN2 trial.
Videolaryngoscopes with an operating channel may improve the intubation success rate in critically ill patients. We aimed to compare four channelled videolaryngoscopes to the Macintosh laryngoscope used for intubation of a high-fidelity simulation mannikin, in a scenario that simulated critical illness due to acute respiratory failure. Of the 79 residents who participated, 54 were considered inexperienced with orotracheal intubation. Each participant used all five devices in random order. The first-pass success rate was 97.5% [95% CI 91.1-99.7] for Airtraq™, KingVision™, and Pentax AWS200™, 92.4% [95% CI 84.2-97.2] for VividTrac VT-A100™, and 70.9% [95% CI 59.6-80.6] for direct Macintosh laryngoscopy. The first-pass success rate was significantly lower with direct Macintosh laryngoscopy than with the videolaryngoscopes (p < 0.0001 for Airtraq™, KingVision™, Pentax AWS200™, and VividTrac VT-A100™). The Airtraq™, KingVision™, and Pentax AWS200™ channelled videolaryngoscopes produced high first-pass success rates with a lower boundary of the 95% CI above 90%. A multicentre, randomised controlled clinical study comparing channelled videolaryngoscopy to direct laryngoscopy should include one of these three videolaryngoscopes.


[The campaign against schistosomiasis].
Like other diseases linked to environment from where men look for supplies of goods, schistosomiases are difficult to control. Means of control are existing (mass treatment, selective treatment, with well tolerated drugs) but to insure the decrease of the prevalence over a long period of time, the strategies are sophisticated and often expensive. Therefore, today the objectives of schistosomiasis control are focused on the prevention and decrease of morbidity rather than on the decrease of transmission. Especially so when the economic, social and cultural levels do not permit to avoid the "pathogenic" behaviours.


Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate-induced cytotoxicity.
Glaucoma is a family of eye disorders whose ultimate cause of vision loss is apoptosis of retinal ganglion cells. Although several etiologies of glaucoma exist, oxidative stress is thought to be a key mechanism by which ganglion cells die. From this perspective, the work presented here was designed to examine the efficacy of 17beta-estradiol and three synthetic estrogen analogues (ZYC-1, ZYC-3, ZYC-10) as retinal ganglion cell neuroprotectants. Compound ZYC-1 and its enantiomer ZYC-10, containing an additional double bond in the steroid C ring of 17beta-estradiol, had similar (ZYC-1) or modestly reduced (ZYC-10) affinity for estrogen receptors compared to the parent estrogen. In the case of ZYC-3, the addition of an adamantyl group to the C2 position of the A ring of estrone abolished its binding to the estrogen receptors. RGC-5 cells (an established clonal rat retinal ganglion cell line) and rat retinas were shown to predominantly express estrogen receptor alpha, with minimal detectable levels of estrogen receptor beta. The affinity of the synthetic compounds for estrogen receptors was as follows: ZYC-3 < ZYC-10 < ZYC-1. An in vitro model of glutamate-induced RGC-5 cell death was used. Glutamate treatment resulted in 50-60% RGC-5 cell death with respect to control untreated cells. 17beta-estradiol and the three estrogen analogues (0.5 to 1.0 microM) protected the RGC-5 cells against glutamate cytotoxicity. The efficacy of neuroprotection by the estrogen analogues was as follows: ZYC-3 > ZYC-1 > ZYC-10. EC(50) values for inhibition of TBARS levels were as follows: ZYC-3 > ZYC-10 > ZYC-1. Furthermore, these compounds worked independent of estrogen receptors, as inclusion of 100 nM ICI 182,780 did not reverse their neuroprotective properties against glutamate insult. These compounds seem to affect neuroprotection via pathways independent of the classical estrogen receptors. The data support the hypothesis that estrogen analogues may be useful in the treatment of neurodegenerative diseases, particularly in neuroprotection of retinal ganglion cells in ocular pathologies such as glaucoma.


Engineered electrical conduction tract restores conduction in complete heart block: from in vitro to in vivo proof of concept.
Cardiac electrical conduction delays and blocks cause rhythm disturbances such as complete heart block, which can be fatal. Standard of care relies on electronic devices to artificially restore synchrony. We sought to create a new modality for treating these disorders by engineering electrical conduction tracts designed to propagate electrical impulses. This study sought to create a new approach for treating cardiac conduction disorders by using engineered electrical conduction tracts (EECTs). Paramagnetic beads were conjugated with an antibody to gamma-sarcoglycan, a cardiomyocyte cell surface antigen, and mixed with freshly isolated neonatal rat ventricular cardiomyocytes. A magnetic field was used to pattern a linear EECT. In an in vitro model of conduction block, the EECT was patterned so that it connected 2 independently beating neonatal rat ventricular cardiomyocyte monolayers; it achieved coordinated electrical activity, with action potentials propagating from 1 region to the other via EECT. Spiking the EECT with heart-derived stromal cells yielded stable structures with highly reproducible conduction velocities. Transplantation of EECTs in vivo restored atrioventricular conduction in a rat model of complete heart block. An EECT can re-establish electrical conduction in the heart. This novel approach could, in principle, be used not only to treat cardiac arrhythmias but also to repair other organs.


Characterization of the secondary structure and melting of a self-cleaved RNA hammerhead domain by 1H NMR spectroscopy.
We have completely assigned the extreme low-field ring-NH nuclear magnetic resonance spectrum of a self-cleaving RNA in the absence of magnesium ions by experiments involving sequential Overhauser enhancements between adjacent base pairs. These assignments substantiate the hammerhead secondary folding model proposed by Symons and co-workers for this class of self-cleaving RNA [Hutchins, C. J., Rathjen, P. D., Forster, A. C., & Symons, R. H. (1986) Nucleic Acids Res. 14, 3627-3640; Forster, A. C. & Symons, R. H. (1987) Cell 49, 211-220; Kneese, P., & Symons, R. H. (1987) in Viroids and Viroid-like Pathogens (Semancick, J. S., Ed.) pp 1-47, CRC Press, Boca Raton, FL]. No resonances due to tertiary base pairs could be identified in the low-field spectrum, and addition of MgCl2 to the sample did not produce additional resonances in this region of the spectrum.


Localization of reference points in electromagnetic tracking data and their application for treatment error detection in interstitial breast brachytherapy.
Electromagnetic tracking (EMT) is a promising technology that holds great potential to advance patient-specific pre-treatment verification in interstitial brachytherapy (iBT). It allows easy determination of the implant geometry without line-of-sight restrictions and without dose exposure to the patient. What it cannot provide, however, is a link to anatomical landmarks, such as the exit points of catheters or needles on the skin surface. These landmarks are required for the registration of EMT data with other imaging modalities and for the detection of treatment errors such as incorrect indexer lengths, and catheter or needle shifts. To develop an easily applicable method to detect reference points in the positional data of the trajectory of an EMT sensor, specifically the exit points of catheters in breast iBT, and to apply the approach to pre-treatment error detection. Small metal objects were attached to catheter fixation buttons that rest against the breast surface to intentionally induce a local, spatially limited perturbation of the magnetic field on which the working principle of EMT relies. This perturbation can be sensed by the EMT sensor as it passes by, allowing it to localize the metal object and thus the catheter exit point. For the proof-of-concept, different small metal objects (magnets, washers, and bushes) and EMT sensor drive speeds were used to find the optimal parameters. The approach was then applied to treatment error detection and validated in-vitro on a phantom. Lastly, the in-vivo feasibility of the approach was tested on a patient cohort of four patients to assess the impact on the clinical workflow. All investigated metal objects were able to measurably perturb the magnetic field, which resulted in missing sensor readings, that is two data gaps, one for the sensor moving towards the tip end and one when retracting from there. The size of the resulting data gaps varied depending on the choice of gap points used for calculation of the gap size; it was found that the start points of the gaps in both directions showed the smallest variability. The median size of data gaps was ⩽8 mm for all tested materials and sensor drive speeds. The variability of the determined object position was ⩽0.5 mm at a speed of 1.0 cm/s and ⩽0.7 mm at 2.5 cm/s, with an increase up to 2.3 mm at 5.0 cm/s. The in-vitro validation of the error detection yielded a 100% detection rate for catheter shifts of ≥2.2 mm. All simulated wrong indexer lengths were correctly identified. The in-vivo feasibility assessment showed that the metal objects did not interfere with the routine clinical workflow. The developed approach was able to successfully detect reference points in EMT data, which can be used for registration to other imaging modalities, but also for treatment error detection. It can thus advance the automation of patient-specific, pre-treatment quality assurance in iBT.


The impact of menopause on health-related quality of life: results from the STRIDE longitudinal study.
We examine the impact of menopausal status, beyond menopausal symptoms, on health-related quality of life (HRQoL). Seven hundred thirty-two women aged 40-65, regardless of health condition or menopausal status, were enrolled from single general internal medicine practice. Women completed annual questionnaires including HRQoL, and menopausal status and symptoms. The physical health composite of the RAND-36 is lower in late peri (45.6, P < .05), early post (45.4, P < .05), and late postmenopausal women (44.6, P < .01), and those who report a hysterectomy (44.2, P < .01) compared to premenopausal women (47.1), with effect sizes of Cohen's d = .12-.23. The mental health composite of the RAND-36 is lower in late peri (44.7, P < .01), early post (44.9, P < .01), and late postmenopausal women (45.0, P < .05) and those who report a hysterectomy (44.2, P < .01) compared to premenopausal women (46.8), with effect sizes of Cohen's d = .15-.20. Findings are comparable adjusted for menopausal symptom frequency and bother. Over a 5-year follow-up period, we found a negative impact of menopause on some domains of HRQoL, regardless of menopausal symptoms. Clinicians should be aware of this relationship and work to improve HRQoL, rather than expect it to improve spontaneously when menopausal symptoms resolve.


Decrease and recovery in cell surface charge induced by anesthetics.
We applied cell electrophoresis to detect the effect of anesthetics on membrane, and clarified the concentration - effect relationship and the term of reversibility. The cell electrophoretic mobility of rat erythrocytes decreased with time of incubation with intravenous anesthetics (thiopental or droperidol) at clinical concentrations and reached a minimum value of 25% reduction in 30 min. The effect changed gradually in the concentration range of 0.5-1000 microgram/ml of thiopental, and changed markedly with 0.3-1 microgram/ml of droperidol. Washing out of the anesthetics and subsequent incubation in serum-containing medium resulted in the complete recovery in the mobility when 5 microgram/ml thiopental or 1 microgram/ml droperidol was used. With high concentration of thiopental (100 microgram/ml) or droperidol (10 microgram/ml, however, unrecovered fraction of cells increased with time of treatment. The critical time for retaining the reversibility was about 2 hr.


Postoperative recurrence of simple goiter and replacement therapy. Study of 210 patients.
The incidence of recurrent goiter after different surgical procedures for colloid-cystic goiter has been studied in 210 patients. The results of the study confirm the high incidence of recurrence (35.7%). This incidence was shown to be higher in patients undergoing more conservative surgery. Furthermore, the incidence resulted also higher in younger patients, while it was lower after postoperative replacement therapy.


Safety assessment of metarrestin in dogs: A clinical candidate targeting a subnuclear structure unique to metastatic cancer cells.
Pancreatic cancer is a leading cause of cancer-related deaths in the U.S. Ninety percent of patients with stage IV pancreatic cancer die within one year of diagnosis due to complications of metastasis. A metastatic potential of cancer cells has been shown to be closely associated with formation of perinucleolar compartment (PNC). Metarrestin, a first-in-class PNC inhibitor, was evaluated for its toxicity, toxicokinetics, and safety pharmacology in beagle dogs following every other day oral (capsule) administration for 28 days to support its introduction into clinical trials. The study consisted of four dose groups: vehicle; 0.25, 0.75 and 1.50 mg/kg/dose. Metarrestin reached its maximum concentration in blood at 3 h (overall median Tmax) across all doses with a mean t1/2 over 168 h of 55.5 h. Dose dependent increase in systemic exposure (Cmax and AUClast) with no sex difference was observed on days 1 and 27. Metarrestin accumulated from Day 1 to Day 27 at all dose levels and in both sexes by an overall factor of about 2.34. No mortality occurred during the dosing period; however, treatment-related clinical signs of toxicity consisting of hypoactivity, shaking/shivering, thinness, irritability, salivation, abnormal gait, tremors, ataxia and intermittent seizure-like activity were seen in both sexes at mid and high dose groups. Treatment-related effects on body weight and food consumption were seen at the mid and high dose levels. Safety pharmacology study showed no treatment-related effects on blood pressure, heart rate, corrected QT, PR, RR, or QRS intervals, or respiratory function parameters (respiratory rate, tidal volume, minute volume). There were no histopathological changes observed, with the exception of transient thymic atrophy which was considered to be non-adverse. Based primarily on clinical signs of toxicity, the No Observed Adverse Effect Level (NOAEL) in dogs was considered to be 0.25 mg/kg metarrestin after every other day dosing for 28 days with a mean of male and female Cmax = 82.5 ng/mL and AUClast = 2521 h*ng/mL, on Day 27.


DISPERSAL AND GENETIC STRUCTURE IN KANGAROO RATS.
We used spatial autocorrelation of allele frequencies to examine local structure in a population of bannertailed kangaroo rats for which Wright's isolation-by-distance model seems applicable, and for which we can estimate neighborhood size based on 10 years of data on demography and dispersal. The uniform dispersion and strong philopatric tendencies of this species provide a test case for the idea that restricted dispersal can lead to local genetic structure in small mammals. Whether we considered such complications as nonnormal dispersal distances, variation in lifetime reproductive success, fluctuating population density, and adult as well as juvenile dispersal, our estimate of effective population size was fewer than 15 animals. Nevertheless, data from four polymorphic allozyme loci analyzed over a range of separations between 50 m (approximately one home range diameter) and 1,000 m detected no evidence for spatial clustering of alleles. One resolution of this apparent paradox is that "gamete dispersal," caused by the movements of males away from their residences during the breeding season, may be a significant (and unmeasured) component of gene dispersal. Our analyses also demonstrate that a decline in population density may actually increase neighborhood size. A more general implication is that even extremely philopatric mammals have effective population sizes large enough to prevent the development of local genetic structure.


Scaling of theory-of-mind understandings in Chinese children.
Prior research demonstrates that understanding of theory of mind develops at different paces in children raised in different cultures. Are these differences simply differences in timing, or do they represent different patterns of cultural learning? That is, to what extent are sequences of theory-of-mind understanding universal, and to what extent are they culture-specific? We addressed these questions by using a theory-of-mind scale to examine performance of 140 Chinese children living in Beijing and to compare their performance with that of 135 English-speaking children living in the United States and Australia. Results reveal a common sequence of understanding, as well as sociocultural differences in children's developing theories of mind.


Electrophysiologic manifestations of cardiac sarcoidosis.
Cardiac involvement in sarcoidosis patients is frequently unrecognized with ventricular arrhythmias and sudden cardiac death (SCD) sometimes occurring as its initial presentation. Early involvement of an electrophysiologist as part of a multidisciplinary team is essential to screening, risk stratification, and management of cardiac sarcoidosis patients. This review outlines potential manifestations of cardiac sarcoidosis, as well as diagnostic and treatment strategies. Recent retrospective analyses have shown that the incidence of atrioventricular block, atrial tachyarrhythmias, and ventricular tachyarrhythmias in these patients is substantial. In addition to advanced cardiac imaging, there is a role for ECG, signal-averaged ECG, ambulatory telemetry monitoring, and electrophysiologic testing in the initial evaluation of a patient with suspected cardiac sarcoidosis. There have been recent investigations into the role of implantable cardioverter-defibrillators (ICDs) for SCD prevention with a high rate of appropriate therapies observed. Immunosuppressive therapy, antiarrhythmic drugs, and catheter ablation each also have a role in the reduction of overall arrhythmic burden. The electrophysiologist's approach to a patient with cardiac sarcoidosis can aid in diagnosis, risk stratification, and management with antiarrhythmic therapy, catheter ablation, and ICD implantation for the prevention of SCD.


An unexpected case of hypercalcaemia and hilar fullness.
Hypercalcaemia, a condition with abnormally raised calcium levels, is commonly caused by cancer, immobility, certain supplements and other diseases such as sarcoidosis. In this case report, we present a 65-year-old female who presented with hypercalcaemia, hilar adenopathy on chest X-ray and a pathological fracture of her ankle that was unexpectedly due to hyperparathyroidism.