Sub-neurotoxic neonatal anoxia induces subtle behavioural changes and specific abnormalities in brain group-I metabotropic glutamate receptors in rats.
Anoxia in the first week of life can induce neuronal death in vulnerable brain regions usually associated with an impairment of cognitive function that can be detected later in life. We set-up a model of subneurotoxic anoxia based on repeated exposures to 100% nitrogen during the first 7 days of post-natal life. This mild post-natal exposure to anoxia specifically modified the behaviour of the male adult rats, which showed an attention deficit and an increase in anxiety, without any impairment in spatial learning and any detectable brain damage (magnetic resonance imaging and histological analysis). Post-anoxic rats showed a reduction in the expression of group-I metabotropic glutamate receptors (i.e. mGlu1 and mGlu5 receptors) in the hippocampus and cerebral cortex, whereas expression of the mGlu 2/3 receptors, the NR1 subunit of NMDA receptors, and the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors was unchanged. mGlu1 and mGlu5 receptor signalling was also impaired in postanoxic rats, as revealed by a reduced efficacy of the agonist (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) to stimulate polyphosphoinositide hydrolysis in hippocampal slices. We conclude that rats subjected to subneurotoxic doses of anoxia during the early post-natal life develop behavioural symptoms that are frequently encountered in the inattentive subtype of the attention deficit hyperactivity disorder, and that group-I mGlu receptors may be involved in the pathophysiology of these symptoms.


Pharmacokinetics and metabolism of natural methylxanthines in animal and man.
Caffeine, theophylline, theobromine, and paraxanthine administered to animals and humans distribute in all body fluids and cross all biological membranes. They do not accumulate in organs or tissues and are extensively metabolized by the liver, with less than 2% of caffeine administered excreted unchanged in human urine. Dose-independent and dose-dependent pharmacokinetics of caffeine and other dimethylxanthines may be observed and explained by saturation of metabolic pathways and impaired elimination due to the immaturity of hepatic enzyme and liver diseases. While gender and menstrual cycle have little effect on their elimination, decreased clearance is seen in women using oral contraceptives and during pregnancy. Obesity, physical exercise, diseases, and particularly smoking and the interactions of drugs affect their elimination owing to either stimulation or inhibition of CYP1A2. Their metabolic pathways exhibit important quantitative and qualitative differences in animal species and man. Chronic ingestion or restriction of caffeine intake in man has a small effect on their disposition, but dietary constituents, including broccoli and herbal tea, as well as alcohol were shown to modify their plasma pharmacokinetics. Using molar ratios of metabolites in plasma and/or urine, phenotyping of various enzyme activities, such as cytochrome monooxygenases, N-acetylation, 8-hydroxylation, and xanthine oxidase, has become a valuable tool to identify polymorphisms and to understand individual variations and potential associations with health risks in epidemiological surveys.


Sex differences in predictors of illness intrusiveness 1 year after a cardiac event.
This prospective study examined sex differences in illness intrusiveness and in baseline predictors of illness intrusiveness in cardiac patients' 1-year postcardiac event. Patients diagnosed with a myocardial infarction (MI) or unstable angina (UA) completed a baseline questionnaire during their hospitalization (139 men and 104 women). Eighty-one men and 67 women completed the follow-up questionnaire 1-year postcardiac event. The questionnaire included measures of illness intrusiveness in three life domains, depressive symptomatology, social support, medical information, risk factors for heart disease, and sociodemographic information. A MANCOVA with the three Illness Intrusiveness subscales as dependent variables, sex as the between-group factor, and partnership status as a covariate found a sex effect for the Intimacy subscale, but not for the Instrumental and the Relationships/Personal Development subscales. Men reported more intrusiveness in the Intimacy domain of their life as compared to women. After controlling for sociodemographic factors and risk factors for heart disease, hierarchical regressions indicated sex differences in baseline predictors of 1-year follow-up illness intrusiveness in the three life domains. For men, being satisfied with support from partner at baseline was associated with less intrusiveness in the Instrumental Life domain 1 year after the cardiac event. For women, surprisingly, more satisfaction with support from their partner at baseline was associated with more intrusiveness in their intimate lives 1 year after their cardiac event. In addition, emotional symptoms of depression at baseline were predictive of increased illness intrusiveness in Relationship/Personal Development and Intimacy domains for men and in Instrumental and Intimacy domains for women. Support from partner may have a differential impact for men and women after a cardiac event. Depressive symptomatology during initial hospitalization, particularly emotional symptoms, is a prominent indicator of illness intrusiveness for both sexes 1 year after the cardiac event.


Transtemporal Investigation of Brain Parenchyma Elasticity Using 2-D Shear Wave Elastography: Definition of Age-Matched Normal Values.
The goal of our research was to assess the possibility of reliable investigation of brain tissue stiffness using ultrasonographic brain parenchyma elastography with an intact temporal bone. We enrolled 108 patients after exclusion of intracranial pathology or healthy volunteers. All patients were subdivided by age into groups: 20-40, 40-60 and >60 y. For statistical analysis, the χ2 test and t-test were used. The mean values, regardless of age and other parameters, were 3.34 kPa (SD = 0.59) on the left side and 3.33 kPa (SD = 0.58) on the right side. We found no correlation between the values, body mass index (r = 0.07, p = 0.48) and sex (t = -0.11, p = 0.91), but we observed a highly significant correlation between the values and age (r = 0.43, p <0.0001). We found ultrasonographic brain parenchyma elastography to be a valid, reproducible and investigator-independent method that reliably determines brain parenchyma stiffness. Normal values should serve as a reference for studies on various intracranial lesions.


Evaluation of sector-specific AWARE characterization factors for water scarcity footprint of electricity generation.
Life Cycle Impact Assessment (LCIA) links the emissions and resource abstractions of a product system or process to potential impacts on the environment through characterization factors (CF). For regionalized impact categories like water-use, the regional CFs can vary over several orders of magnitude within the same country. The aggregated country-level CF, often used in LCIA, represents an average of local CF weighted by the local water consumption of all (or most) human water use including water use by all (or most) economic sectors. There is, however, great variability in spatio-temporal distribution of human water consumption across different industries. This study provides industry-specific water-use CFs for the electricity sector across the US. Our analysis shows that for electricity generation, the use of all-sector aggregated water-use CF would lead to an underestimation of impact scores compared to industry-specific CFs, by two folds. Even within the electricity sector, for two of the major subsectors, electricity based on natural gas and hydroelectricity, the country-level CFs can be significantly different due to the geographic distribution of powerplants. Our findings signify that the use of industry-specific CF can have a high influence in LCIA, especially for impact categories, such as water-use, with great spatio-temporal heterogeneity.


Product formation in the Prato reaction on Sc3N@D(5h)-C80: preference for [5,6]-bonds, and not pyracylenic bonds.
We report here reaction energies and NMR data for the N-tritylpyrrolidino mono-adducts of Sc(3)N@D(5h)-C(80). The pyracylene adduct that was previously suggested to be important for the Prato reaction is ruled out both from energetic and NMR points of view.


The efficacy low dose of prednisolone in the treatment of hyperemesis gravidarum.
To determine whether low dosages of prednisolone are effective in the treatment of outpatients with hyperemesis gravidarum. Eighty pregnant women with gestational ages of 6 to 12 weeks and persistent nausea and vomiting participated. The women were assigned by simple randomization to receive prednisolone 5 mg daily or promethazine 75 mg daily by oral route for 10 days. The severity of nausea, frequency of vomiting per day, sickness and the drugs' side-effects were compared (Fisher's exact test, Mann-Whitney U-test, Odds Ratio test). The women who received promethazine responded better in the first 48 h (p = 0.02). With continuation of the treatment, the difference decreased, and one week after completion of the treatment, the subjects who had received prednisolone had less symptoms. Promethazine reduces the symptoms of hyperemesis gravidarum faster than prednisolone, but during prolonged treatment, prednisolone has at least the same effects on the symptoms and less drug side-effects.


Racial and ethnic disparities in health care-associated Clostridium difficile infections in the United States: State of the science.
Among health care-associated infections (HAIs), Clostridium difficile infections (CDIs) are a major cause of morbidity and mortality in the United States. As national progress toward CDI prevention continues, it will be critical to ensure that the benefits from CDI prevention are realized across different patient demographic groups, including any targeted interventions. Through a comprehensive review of existing evidence for racial/ethnic and other disparities in CDIs, we identified a few general trends, but the results were heterogeneous and highlight significant gaps in the literature. The majority of analyzed studies identified white patients as at increased risk of CDIs, although there is a very limited literature base, and many studies had significant methodological limitations. Key recommendations for future research are provided to address antimicrobial stewardship programs and populations that may be at increased risk for CDIs.


Attachment of metal trications to peptides.
Gas-phase complexes of triply charged metal ions with peptides may be readily produced using electrospray ionization, including for small peptides such as bradykinin and peptides with no basic residues such as insulin chain A. Attachment without charge-reduction is demonstrated for all trications studied: La(3+), Al(3+), Ga(3+), Fe(3+), V(3+), and Cr(3+). The intensities of adducts are often comparable to, or even exceed, those of protonated analogs in any charge state.


Low temperature aqueous electrospray ionization mass spectrometry of noncovalent complexes.
In the present study we describe conditions that permit the characterization of noncovalent protein-substrate complexes in aqueous solution by microspray electrospray ionization-mass spectrometry (ESI-MS), using a heated transfer capillary at low temperature (45 degrees C). Specifically, we examined the binding of calmodulin to two polypeptides; the calmodulin-binding domain of calmodulin-dependent protein kinase II (CamK-II) and melittin. Calmodulin, a well known calcium-binding protein, binds to a number of small amphipathic peptides in a calcium-dependent manner. Our results directly show that both peptides form equimolar complexes with calmodulin only in the presence of calcium. The stoichiometry necessary for the formation of each complex was 1:1:4 for calmodulin:peptide (melittin or CamK-II):Ca2+, respectively. Furthermore, it is demonstrated that the detection of the complex in ESI-MS is source temperature dependent.


Effects of pCIneo and pCEP4 expression vectors on transient and stable protein production in human and simian cell lines.
To support and meet the demand for recombinant proteins early in the drug discovery process, much work has been directed toward improving the methods used for transient gene transfection and expression. A factor which could potentially affect the outcome of experiments is the choice of the expression vector. Conventional vectors such as pCIneo and pcDNA3 have been used frequently. Each of these places the gene of interest under the control of the CMV promoter. An interesting alternative is provided by episomal vectors. For example, the pCEP4 vector contains the gene coding for the Epstein Barr nuclear antigen as well as the EBNA ori P sequence. This combination allows for the episomal replication of the plasmid. In preliminary experiments, we compared transient secreted placental alkaline phosphatase production in 8 cell lines from 3 different species using the pCIneo vs. pCEP4 vectors and found the utility of the pCEP4 vector to be limited to the human 293 EBNA cell line. In this paper, we have compared the two vectors in six cell lines of simian and human origin, measuring the transient production of secreted placental alkaline phosphatase and human hepatocyte growth factor. In general, the pCEP4 vector produced higher amounts of both proteins in transient transfections. Results were particularly pronounced in the HEK 293 and 293 EBNA cell lines. Stable pools of cells (uncloned) expressing human hepatocyte growth factor were isolated using pCIneo and pCEP4 and protein production levels were compared to those seen in transient transfections. Stable expression with pCEP4 was found to produce the highest levels of human hepatocyte growth factor in 3 of 4 cell lines. Finally, electroporation and FuGENE(TM)6(Roche, Indianapolis IN) as transfection methods were compared measuring transient production of secreted placental alkaline phosphatase, human hepatocyte growth factor, and green fluorescent protein. FuGENE produced higher protein concentrations in less time than electroporation for all 3 proteins.


Investigations of chorionic villi after chorionic villus sampling (CVS). Correlation of morphological with clinical and laboratory data.
This report documents the first 262 cases of chorionic villus sampling (CVS) performed in parallel with cytogenetic and morphological investigations. Histomorphological examination of these CVS specimens gave suitable results in about 96% (251 cases). Of the latter, 201 samples (80.1%) exhibited villi and 176 (70.1%), maternal tissue. Viability and maturation of the chorionic villi were determined light microscopically even in cases with few villus trees. Smooth avascular villi with poorly defined margins observed under an inverted microscope, less than 10 mitoses after short-term incubation, and reduced growth of cell cultures were significantly correlated with sampling at the chorion laeve by means of histomorphologic criteria. Villi from cases exhibiting cytogenetically proved chromosomal abnormalities were characterized by molar degeneration or stromal fibrosis, or both, in 4 out of 9 cases, including 3 mosaics. In early abortions (within 3 weeks after CVS), an unexpectedly high rate of pathohistological changes within maternal tissue was evident. These results need further confirmation by investigation of a greater number of samples with immunohistochemical and morphometric methods.


Rinsing with chlorhexidine may reduce incidence of dry socket after third molar surgery.
Medline and the Science Citation Index were used and searches were made by hand for studies published in any language. Studies included were human clinical trials evaluating the effect of a chlorhexidine (CHX) rinse on the incidence of alveolar osteitis (AO), following extraction of mandibular third molars, if they randomly assigned individuals to control and CHX rinse groups that used similar criteria to diagnose AO. Studies were screened by three examiners independently. Due to protocol differences, studies were separated into two groups. Group 1 included studies that evaluated subjects who rinsed with CHX only on the day of surgery and Group 2 studies that evaluated patients who used multiple rinses with CHX. The relative risk for the single-rinse group was 1.36 (95% confidence interval (CI), 0.80-2.33; P>0.05), whereas for the multiple-rinse group, relative risk was 1.90 (95% CI, 1.46-2.47, P<0.05). It was not possible to determine if a single rinse with CHX on the day of surgery significantly reduced the incidence of AO. The results of this study do, however, support the conclusion that rinsing at least on the day of surgery and for several days following the removal of the teeth reduces the incidence of AO associated with the extraction of mandibular third molars. The minimum number of days of rinsing needed to produce this effect could not be determined by this analysis. Further studies using a standard definition for AO, and stratification of patients by gender, difficulty of extraction, smoking etc., are needed to determine the best use for CHX rinses in subjects having the mandibular third molar removed.


Localized and Whole-Room Effects of Portable Air Filtration Units on Aerosol Particle Deposition and Concentration in a Classroom Environment.
In indoor environments with limited ventilation, recirculating portable air filtration (PAF) units may reduce COVID-19 infection risk via not only the direct aerosol route (i.e., inhalation) but also via an indirect aerosol route (i.e., contact with the surface where aerosol particles deposited). We systematically investigated the impact of PAF units in a mock classroom, as a supplement to background ventilation, on localized and whole-room surface deposition and particle concentration. Fluorescently tagged particles with a volumetric mean diameter near 2 μm were continuously introduced into the classroom environment via a breathing simulator with a prescribed inhalation-exhalation waveform. Deposition velocities were inferred on >50 horizontal and vertical surfaces throughout the classroom, while aerosol concentrations were spatially monitored via optical particle spectrometry. Results revealed a particle decay rate consistent with expectations based upon the reported clean air delivery rates of the PAF units. Additionally, the PAF units reduced peak concentrations by a factor of around 2.5 compared to the highest concentrations observed and led to a statistically significant reduction in deposition velocities for horizontal surfaces >2.5 m from the aerosol source. Our results not only confirm that PAF units can reduce particle concentrations but also demonstrate that they may lead to reduced particle deposition throughout an indoor environment when properly positioned with respect to the location of the particle source(s) within the room (e.g., where the largest group of students sit) and the predominant air distribution profile of the room.


Design, synthesis, and biological evaluation of novel histone deacetylase 1 inhibitors through click chemistry.
We report the design, synthesis, and biological evaluation of a new series of HDAC1 inhibitors using click chemistry. Compound 17 bearing a phenyl ring at meta-position was identified to show much better selectivity for HDAC1 over HDAC7 than SAHA. The compond 17 also showed better in vitro anticancer activities against several cancer cell lines than that of SAHA. This work could serve as a foundation for further exploration of selective HDAC inhibitors using the compound 17 molecular scaffold.


[Which factors influence screening practices for female cancer in France?].
The two aims of the study were, first to estimate the declared two-year coverage of breast cancer and cervical cancer screenings, and second to determine the main factors influencing female cancer screening behaviors. Three groups of women from the 2003 French decennial health interview survey were analyzed: 3378 women aged 50-74 years who answered the question on mammography use, 7912 women aged 25-65 years who answered the question on Pap-smear use, and 2528 women aged 50-65 years who answered both questions. The declared coverage of breast cancer screening was 71.2%, the declared coverage of cervical cancer screening was 76.3%. Almost 18% of women declared having undergone neither a mammography nor a Pap-smear in the last two years. The main factor linked to a more frequent practice of one or both cancer screenings (breast or cervix) was to have undergone recently the other screening. The other factors linked to mammography use were mainly healthcare and practitioner access variables. Those linked to Pap-smear use were mainly socioeconomic and socio-demographic variables, healthcare and practitioner access variables being also linked. The main factors linked to having undergone none of these two screenings were of financial nature, particularly household income and home ownership. The study showed that it is appropriate to communicate on both screenings at the same time since they have a positive effect each other. Finally, practitioners continue to play a central role in collecting information on cancer screenings and encouraging screening in women not regularly screened.


A laser-aligned method for anthropometry of hands.
We have developed a laser-aligned measuring device to facilitate the measurement of linear hand dimensions. Our objective has been to make a simple, clinically applicable device for anthropometry of the hands in patients with arthritis in order to gauge the progression of hand deformities. The system provides an alternative to the use of rules, tapes, photogrammetry and least-squares devices which have previously been applied to hand measurements. The system delivers results which are not significantly different from those measured with rules and callipers and has a similar level of accuracy. The use of laser pointers for alignment facilitates measurements which necessitate picking the highest point of the hand. The device is portable and simple to use in the clinic. We have used it to measure hand dimensions in normal subjects and patients with arthritis. However, the system could equally well be used to facilitate measurement of other objects with an irregular surface profile.


Treatment of a compound calcaneus fracture Sanders IV with an external circular fixator and calcaneal osteotomy.
Compound Gustilo-type III intra-articular calcaneus fractures are challenging to treat. Anatomical reduction of the subtalar joint increases the chances of a better functional outcome and is traditionally achieved by an open reduction and plating. Conversely, ORIF is associated with a high risk of infection and even amputation. In our case study, we present the treatment of a Gustilo-type III intra-articular calcaneus fracture with a circular external fixator and a temporary antibiotic cement spacer for fracture reduction and stabilization. Active bio-glass was implanted to fill bone loss and to prevent infection. A closing-wedge calcaneal tuberosity osteotomy was used to facilitate wound closure. We paid special attention to reducing the posterior facet. The patient returned to work and full ambulation five months post-injury.


N-glycan branching enzymes involved in cancer, Alzheimer's disease and COPD and future perspectives.
Over the past 3 decades, our group has been involved in studies related to the biosynthesis of N-glycan branching and related glycosyltransferases and have purified most of these Golgi-derived enzymes to homogeneity using classical purification methods and cloned the cDNA of GnT-III, IV, V, VI and Fut8 except GnT-IX(Vb) which was obtained by homology cloning. Based primarily on our data, we briefly summarize the significance of three major enzymes and discuss perspectives for future studies on the occasion of Ernesto's 90th birthday celebration.


Silver-Coated Disordered Silicon Nanowires Provide Highly Sensitive Label-Free Glycated Albumin Detection through Molecular Trapping and Plasmonic Hotspot Formation.
Glycated albumin (GA) is rapidly emerging as a robust biomarker for screening and monitoring of diabetes. To facilitate its rapid, point-of-care measurements, a label-free surface-enhanced Raman spectroscopy (SERS) sensing platform is reported that leverages the specificity of molecular vibrations and signal amplification on silver-coated silicon nanowires (Ag/SiNWs) for highly sensitive and reproducible quantification of GA. The simulations and experimental measurements demonstrate that the disordered orientation of the nanowires coupled with the wicking of the analyte molecules during the process of solvent evaporation facilitates molecular trapping at the generated plasmonic hotspots. Highly sensitive detection of glycated albumin is shown with the ability to visually detect spectral features at as low as 500 × 10-9 m, significantly below the physiological range of GA in body fluids. Combined with chemometric regression models, the spectral data recorded on the Ag/SiNWs also allow accurate prediction of glycated concentration in mixtures of glycated and non-glycated albumin in proportions that reflect those in the bloodstream.


Phosphate binding protein as the biorecognition element in a biosensor for phosphate.
This work explores the potential use of a member of the periplasmic family of binding proteins, the phosphate binding protein (PBP), as the biorecognition element in a sensing scheme for the detection of inorganic phosphate (Pi). The selectivity of this protein originates from its natural role which, in Escherichia coli, is to serve as the initial receptor for the highly specific translocation of Pi to the cytoplasm. The single polypeptide chain of PBP is folded into two similar domains connected by three short peptide linkages that serve as a hinge. The Pi binding site is located deep within the cleft between the two domains. In the presence of the ligand, the two globular domains engulf the former in a hinge-like manner. The resultant conformational change constitutes the basis of the sensor development. A mutant of PBP (MPBP), where an alanine was replaced by a cysteine residue, was prepared by site-directed mutagenesis using the polymerase chain reaction (PCR). The mutant was expressed, from plasmid pSD501, in the periplasmic space of E. coli and purified in a single chromatographic step on a perfusion anion-exchange column. Site-specific labeling was achieved by attaching the fluorophore, N-[2-(1-maleimidyl)ethyl]-7-(diethylamino)coumarin-3-carboxamide (MDCC), to the protein through the sulfhydryl group of the cysteine moiety. Steady-state fluorescence studies of the MPBP-MDCC conjugate showed a change in the intensity of the signal upon addition of Pi. Calibration curves for Pi were constructed by relating the intensity of the fluorescence signal with the amount of analyte present in the sample. The sensing system was first developed and optimized on a spectrofluorometer using ml volumes of sample. It was then adapted to be used on a microtiter plate arrangement with microliter sample volumes. The system's versatility was finally proven by developing a fiber optic fluorescence-based sensor for monitoring Pi. In all three cases the detection limits for the analyte were in the sub-microMolar range. It was also demonstrated that the sensing system was selective for phosphate over other structurally-similar anions, paving the way for the design and development of a new family of biosensors utilizing the specific binding properties of periplasmic proteins.


Synthesis, characterization and cytotoxic activity on breast cancer cells of new half-titanocene derivatives.
A series of novel titanocene-complexes has been prepared and evaluated for their growth regulatory effects in MCF7 and SkBr3 breast cancer cells. The capability of some of these compound to elicit relevant repressive effects on cancer cell growth could be taken into account towards novel pharmacological approaches in cancer therapy.


Improving Minimally Invasive Adrenalectomy: Selection of Optimal Approach and Comparison of Outcomes.
Minimally invasive adrenalectomy is commonly performed by either a transperitoneal laparoscopic (TLA) or posterior retroperitoneoscopic (PRA) approach. Our group described the technique for robot-assisted PRA (RAPRA) in 2010. Few studies are available that directly compare outcomes between the available operative approaches. We reviewed our results for minimally invasive adrenalectomy using the three different approaches over a 10-year period. Between January 2005 and April 2015, 160 minimally invasive adrenalectomies were performed. Clinicopathologic data were prospectively collected and retrospectively analyzed. The primary endpoints evaluated were operative time, blood loss, length of stay (LOS), and morbidity. The study included 67 TLA, 76 PRA, and 17 RAPRA procedures. Tumor size for PRA/RAPRA was smaller than for patients undergoing TLA (2.38 vs 3.6 cm, p ≤ 0.0001). Procedure time was shorter for PRA versus TLA (133.3 vs 152.8 min, p = 0.0381), as was LOS (1.85 vs 2.82 days, p = 0.0145). Procedure time was longer in RAPRA versus TLA/PRA (177 vs 153/133 min, p = 0.008), but LOS was significantly decreased (1.53 vs 2.82/1.85 days, p = 0.004). Minimally invasive adrenalectomy is associated with expected excellent outcomes regardless of approach. In our series, the posterior approach is associated with decreased operative time and LOS. Robotic technology provides potential advantages for the surgeon at the expense of more complex setup requirements and costs. Further study is required to demonstrate clear benefit of one surgical approach. Utilization of the entire spectrum of available operative techniques can allow for selection of the optimal approach based on individual patient factors.


Optimization of a minimal sample preparation protocol for imaging mass spectrometry of unsectioned juvenile invertebrates.
Tissue sections have long been the subject matter for the application of imaging mass spectrometry, but recently the technique has been adapted for many other purposes including bacterial colonies and 3D cell culture. Here, we present a simple preparation method for unsectioned invertebrate tissue without the need for fixing, embedding, or slicing. The protocol was used to successfully prepare a Hawaiian bobtail squid hatchling for analysis, and the resulting data detected ions that correspond to compounds present in the host only during its symbiotic colonization by Vibrio fischeri.


[Nature of the sensitizing influence of urea on the effects of catecholamines].
Tests conducted on aortic strips of rabbits, portal veins and musculus rectococcygeus in rats showed the urea to nonspecifically increase the effects of norepinephrine at the expense of a greater calcium permeability of membranes and, possibly, also at the expense of a higher sensitivity of the myosin adenosine-triphosphatase to the action of calcium ions without affecting the function of adrenoreceptors.


Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).
Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. Cancer Research UK, MRC Clinical Trials Unit.


Poisoning with the North American Jack O'Lantern mushroom, Omphalotus illudens.
Ingestion of Jack O'Lantern mushrooms by fourteen people led to vomiting in 8, diarrhea in 5, weakness in 2. Tiredness, the feeling of weakness and being cold occurred in 8. Recovery was complete within 18 hours.


Monitoring of DDT in Agricultural Soils under Organic Farming in Poland and the Risk of Crop Contamination.
The analysis of 142 agricultural soil samples collected in organic farms across Poland with the intent to evaluate the level of DDT contamination resulted in more than 80% of the soils containing DDT. The ΣDDT (sum of all metabolites and isomers) concentration ranged between 0.005 and 0.383 mg/kg ΣDDT, with an average value of 0.064 mg/kg ΣDDT. However, the majority of plant samples collected from the crops growing on the sampled soils did not contain detectable DDT residues. The high DDT pollution levels detected in samples from four voivodeships (regions) among those monitored have been hypothesised to be linked to horticultural productions occurring to the sampled fields and typical of those regions, particularly in big-sized farms, during the period of DDT application, as well as the number of pesticides landfills present in these voivodeships. The elaboration of the o,p'-DDT/p,p'-DDT and DDT/(DDE + DDD) ratios to appraise the source or the period of contamination suggested that the contamination originated from past use of DDT rather than from impurities of more recent applications of other formulated substances. Such outcome thus suggests that the risk of contamination of organic products is likely derived from general environmental pollution levels rather than from the use of unauthorised substances in organic farming productions. Data from a trial with artificial contamination of soils indicated that using the DDT/(DDE + DDD) ratio in the presence of a low level of contamination could be less reliable than in highly contaminated soils.


Muscarinic receptors are involved in LMM3 tumor cells proliferation and angiogenesis.
Angiogenesis is a process of new blood vessel development from pre-existing vasculature and it plays an essential role in tumor growth and metastases. Here, we investigate the expression of muscarinic acetylcholine receptors (mAchR) and their participation in tumor cell proliferation and angiogenesis ability. Saturation binding assays with the tritiated muscarinic antagonist quinuclidinyl benzilate indicate that LMM3 cells derived from a murine mammary adenocarcinoma express a single class of functional mAchR. Competition binding assays with selective muscarinic antagonists indicate a predominance of M3 receptor subtype. The muscarinic agonist carbachol (CARB) stimulates LMM3 cell proliferation in a concentration dependent manner. The maximal effect induced by 10(-9)M CARB was totally blunted by atropine and by the selective M3 and M1 antagonists, para-fluoro hexahydro sila-difenidol (pf-HHSiD) and pirenzepine, respectively. In addition, pf-HHSiD completely blocked in vivo CARB-induced neovascular formation and vascular endothelial growth factor-A in LMM3 tumor cells. We can conclude that mAchR expressed in LMM3 mammary tumor cells positively regulate proliferation and angiogenesis required for tumor progression.


Glycosaminoglycan variants in the C2 muscle cell line.
Using a replica technique, we have isolated and characterized five genetic variants of the C2 mouse muscle cell line that are defective in incorporation of radiolabeled sulfate into glycosaminoglycans (GAGs). The variants incorporate free sulfate into GAGs at 5-20% of wild-type levels. None of the variants is defective in sulfate transport across the cell membrane, and in no case could the deficit in incorporation of sulfate be reversed by addition of an artificial initiator of GAG biosynthesis, p-nitrophenyl beta-D-xyloside. Analysis of the incorporation of [3H]glucosamine into GAGs by the variants revealed three different patterns: one variant incorporated [3H]glucosamine at the wild-type level; one, S27, at a severely reduced level; and three at intermediate levels. Four of the five variants showed marked deficits in their ability to differentiate and fuse. The remaining variant, S27, formed multinucleated myotubes and expressed acetylcholine receptor with a normal time course. Differentiation of the first four variants could not be restored by addition of exogenous GAGs or extracellular matrix. Because of the important roles that GAGs and proteoglycans are thought to play in the differentiation of muscle, these genetic variants should serve as useful tools in functional analyses of these molecules.


Effects of anticonvulsants on soman-induced epileptiform activity in the guinea-pig in vitro hippocampus.
Seizures arising from acetylcholinesterase inhibition are a feature of organophosphate anticholinesterase intoxication. Although benzodiazepines are effective against these seizures, alternative anticonvulsant drugs may possess greater efficacy and fewer side-effects. We have investigated in the guinea-pig hippocampal slice preparation the ability of a series of anticonvulsants to suppress epileptiform bursting induced by the irreversible organophosphate anticholinesterase, soman (100 nM). Carbamazepine (300 microM), phenytoin (100 microM), topiramate (100-300 microM) and retigabine (1-30 microM) reduced the frequency of bursting but only carbamazepine and phenytoin induced a concurrent reduction in burst duration. Felbamate (100-500 microM) and clomethiazole (100-300 microM) had no effect on burst frequency but decreased burst duration. Clozapine (3-30 microM) reduced the frequency but did not influence burst duration. Levetiracetam (100-300 microM) and gabapentin (100-300 microM) were without effect. These data suggest that several compounds, in particular clomethiazole, clozapine, felbamate, topiramate and retigabine, merit further evaluation as possible treatments for organophosphate poisoning.


Relationship between serum interleukin-1beta levels and acute phase response proteins in patients with familial Mediterranean fever.
The aim of this study was to investigate whether serum levels of interleukin-1beta (IL-1beta) has any possible correlation on inflammatory parameters such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fibrinogen concentration in patients with familial Mediterranean fever (FMF) patients during attack-free period. The serum levels of IL-1beta, as an indicator of cytokines status, and the acute phase response proteins, CRP, ESR and fibrinogen levels were evaluated in 35 attack-free patients with FMF and 25 healthy volunteers. Serum IL-1beta levels were significantly higher in patients with FMF than control subjects (P = 0.018). There was no statistically significant difference in the serum levels of ESR, CRP and fibrinogen between two groups (P = 0.181, P = 0.816, P = 0.686, respectively). There was a significant correlation between IL-1beta and CRP (r = 0.513, P = 0.002) values of FMF group. In conclusion, our results confirm the presence of increased IL-1beta levels in FMF patients during attack-free period. Serum IL-1beta values seems to correlate with CRP levels. The elevation of IL-1beta levels may be important in monitoring subclinical inflammation of attack free period in FMF patients.


Leishmania mexicana: distribution of intramembranous particles and filipin sterol complexes in amastigotes and promastigotes.
The density and distribution of intramembranous particles was analyzed in freeze fracture replicas of the plasma membrane of amastigotes, and infective as well as noninfective promastigotes of Leishmania mexicana amazonensis. The density of intramembranous particles on both protoplasmic and extracellular faces was higher in infective than in noninfective promastigotes and it was lower in amastigotes than in promastigotes. Amastigotes purified immediately after tissue homogenization were surrounded by a membrane which corresponded to the membrane which lined the endocytic vacuoles where the parasites were located within the tissue macrophages. Aggregation of the particles was seen in the flagellar membrane at the point of emergence of the flagellum from the flagellar pocket. Differences in the organization of the particles were seen in the membrane which lined the flagellar pocket of amastigotes and promastigotes. The polyene antibiotic, filipin, was used as a probe for the detection of sterols in the plasma membrane of L. m. amazonensis. The effect of filipin in the parasite's structure was analyzed by scanning electron microscopy and by transmission electron microscopy of thin sections and freeze fracture replicas. Filipin sterol complexes were distributed throughout the membrane which lined the cell body, the flagellar pocket, and the flagellum. No filipin sterol complexes were seen in the cell body-flagellar adhesion zone. The density of filipin sterol complexes was lower in the membrane lining the flagellum than in that lining the cell body of promastigotes.


Neuropathology and neurovirulence of canine distemper virus plaque isolates in the hamster.
The relationship between neuropathological abnormalities, antibody response and neurovirulence of plaque isolates has been studied in an experimental model of canine distemper in the hamster. Genetic virus variance influenced neurovirulence and the experimental evidence supports the hypothesis that the mechanism of this effect may be through the modulating effect of circulating antibody. Large plaque virus (LPV) produced severe encephalitis with little early antibody response and a high degree of pathological abnormality. Small plaque virus (SPV) produced mild chronic encephalitis and early antibody response. Microscopically, histological abnormalities in this group were qualitatively similar to those seen with LPV but generally of lesser degree. Immunosuppression in SPV infected animals increased the severity of the encephalitis, reflected by the increase in inflammation and inclusion formation. Combined SPV and LPV infection produced high antibody levels and less severe disease than LPV infection alone with an intermediate pattern of histological abnormality.


Uroradiologic evaluation of children with urinary tract infection: are both ultrasonograpy and renal cortical scintigraphy necessary?
To compare the findings of renal ultrasonography (RUS), 99mTc glucoheptonate renal scan (GHS), and voiding cystourethrography (VCUG) in children with urinary tract infection. Prospective, masked, clinical study. Single center, multidisciplinary, inpatients. Consecutive cases (N = 50) of children aged 2 months to 15 years (8 boys, 42 girls) with pyelonephritis in whom uroradiologic investigation was indicated. All patients underwent GHS, 48 had RUS, and 2 had intravenous pyelography. All but one of the patients had a VCUG. Fifteen children were found to have vesicoureteral reflux (6 unilaterally, 9 bilaterally). Of 96 kidneys evaluated by both GHS and RUS, 53 were abnormal by GHS versus 28 by RUS (p < 0.001). Findings of both GHS and US were normal in 36 kidneys and abnormal in 21 kidneys. In 32 kidneys only GHS showed abnormalities. In 7 kidneys only RUS showed abnormalities; 5 of them had mild to moderate pelvic dilation caused by reflux, which was confirmed in all 5 by VCUG. The VCUG demonstrated reflux in another four units with normal GHS and RUS findings. All combined, GHS and VCUG detected 62 of 64 abnormal renal units (96.9%). In the other two cases, RUS showed only focal hyperechogenicity of questionable importance. In the event that one elects to use GHS for the uroradiologic evaluation of children with urinary tract infection, it can be supplemented by VCUG alone, and RUS can be saved for special cases.


Spray-on-skin cells in burns: a common practice with no agreed protocol.
Cultured epithelial autograft (CEA) has been used for skin coverage after burn wound excision since 1981. It is used in burn units and centres throughout the U.K.; however, there appears to be no agreed standards of practice. We aimed to investigate the experience and current practice with its usage in the management of acute burn injury. An online survey was sent to twenty-five burns consultants in the U.K., who are members of the British Burn Association. We received 14 responses. Rarely have the responders agreed to the same practice in most of the questions. Different choices were given by responders with regards the indications for cell culture, techniques used, primary and secondary dressings used, first wound review timing, and measures used to evaluate outcomes. In the current economic environment, the NHS needs to rationalize services on the basis of cost effectiveness. CEA is an expensive procedure that requires an adequately sterile laboratory, special equipments and highly experienced dedicated staff. When dealing with expensive management options, it is important to have an agreed protocol that can form the standard that can be referred to when auditing practices and results to improve burn management and patients' care.


Potential ecological risk assessment of heavy metals associated with abattoir liquid waste: A narrative and systematic review.
The article presents a narrative and systematic review of the potential ecological risk assessment of heavy metals associated with abattoir liquid waste for knowledge advancement. The narrative review primarily focused on (i) An overview of abattoir operations; (ii) Characteristics of abattoir liquid waste; (iii) Heavy metals in the liquid waste and their health effects; (iv) Environmental impacts of abattoir liquid waste; and (v) Potential ecological risk index (RI) methodology. These provided essential literature for the systematic review. Using exclusive/inclusive criteria, 15 abattoirs that satisfied the eligibility criteria, all located in Nigeria, were used for the systematic review with meta-analysis/meta-regression. Comparative multiple linear meta-regression analyses were used to quantify the heterogeneity variances between the abattoirs based on standardized RIs (SRIs; effect sizes) using eight tau (τ) estimators in R metafor. The effects of three standardized moderators─ number of metals, metal concentrations, and relative distances between the abattoirs and a pristine environment, Gashaka-Gumti National Park (GNP), were also analyzed. The Sidik-Jonkman (SJ) estimator yielded a realistic output, and the current research findings were based on this estimator. The Cochran statistic (QE) suggested an absence of heterogeneity(p>0.99). Between-study heterogeneities, quantified by H2 (1.05), I2 (4.76%), and τ2 (0.0032 ± 0.0032 (SE)) statistics were very low, practically suggesting complete homogeneity. The moderators accounted for R*2 of 95.73% of the total explanatory capacity of the model. The beta coefficients of the moderators and intercept were significant (p-values: 0.009-0.0004). While the first two moderators showed in-phase relations with the SRIs, the third indicated an out-of-phase relation. Such links suggest the existence of abattoir-environment interactive processes. Although the abattoirs are spatially distinct and independent, their operations showed evidence-based homogeneity and posed high ecological risks. Hence, environmental legislation should be strictly enforced while ensuring human settlements are sited reasonably from abattoirs.


Assessment of the Cu(II) and Pb(II) removal efficiency of aqueous solutions by the dry biomass Aguapé: kinetics of adsorption.
Plant-based materials are promising adsorbents for treating liquid effluents. This study describes the kinetic and equilibrium parameters that best represent the copper(II) and lead(II) removal process by Eichhornia crassipes (Aguapé) dry biomass from aqueous solution, using a batch adsorption system. The plants were washed, dried, and reduced to small particles. The adsorption kinetics were assessed by varying the metal concentrations in 5, 10, and 20 mg L-1 and a control treatment (without metals) with a mixture contact time of between 5 and 720 min. Equilibrium data were fitted to the Langmuir and Freundlich models. Kinetic assay revealed fast adsorption: kinetic equilibrium was attained within 2 h with a removal efficiency of ~ 60%. The results demonstrated a fast recovery cycle of metals using the biosorbent. The biomass of E. crassipes is low cost with potential for use as a biosorbent to remove metals from solutions.


Macathioureas A-D, four new thiourea analogues from the roots of Lepidium meyenii.
Macathioureas A-D (1-4), four new thiourea derivatives with a carbamothioylpyrrolidine-2-carboxamide framework, were isolated from the roots of Lepidium meyenii (Maca) collected from Qujing, Yunnan Province of China. Their structures were identified based on extensive spectroscopic data, including 1D NMR, 2D NMR, and HRESIMS techniques. Their absolute configurations were assigned as 7S by the comparison of the experimental and predicted electronic circular dichroism (ECD) spectra. All the thiourea analogues were tested for their cytotoxicities against five human cancer cell lines. However, no significant activities were detected at concentrations up to 40 μM.


[Cryptococcosis in AIDS: therapeutic concepts].
Cryptococcosis is the most common life-threatening mycosis with AIDS. The combination therapy based on amphotericin B and flucytosine is furthermore the therapy of first choice, even after introduction of fluconazole. With a therapy maintained over a period of 6 weeks the combination is nearly always successful; a shorter treatment period leads to minor treatment success. Since no elimination of the pathogen is possible in cryptococcosis with AIDS a permanent relapse prevention is necessary. In this prevention strategy fluconazole is highly effective and at present the drug of first choice; it is as effective as amphotericin B. An additional advantage is the possibility of oral application.


GATA-3 regulates the self-renewal of long-term hematopoietic stem cells.
The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled. Relocation depended on signaling via the mitogen-activated protein kinase p38 and was associated with a diminished capacity for long-term reconstitution after transfer into irradiated mice. Deletion of Gata3 enhanced the repopulating capacity and augmented the self-renewal of long-term HSCs in cell-autonomous fashion without affecting the cell cycle. Our observations position GATA-3 as a regulator of the balance between self-renewal and differentiation in HSCs that acts downstream of the p38 signaling pathway.


Mitogenic effect of prostaglandin E1 in Swiss 3T3 cells: role of cyclic AMP.
Addition of prostaglandin E1 (PGE1) to quiescent cultures of Swiss 3T3 cells rapidly elevates the intracellular levels of cAMP and increases the activity of adenylate cyclase in particulate fractions of these cells. In the presence of insulin, PGE1 stimulates the reinitiation of DNA synthesis. Both effects (increase in cellular cAMP and stimulation of DNA synthesis) are markedly potentiated by 1-methyl-3-isobutyl xanthine (IBMX) or by 4-(3-butoxy-4 methoxy benzyl)-2-imidazolidine (Ro 20-1724), both of which are potent inhibitors of cyclic nucleotide phosphodiesterase activity. In the presence of 50 microM IBMX, PGE1 caused a dose-dependent increase in cAMP levels and in [3H]thymidine incorporation into acid-insoluble material at concentrations (5-50 ng/ml) that are orders of magnitude lower than those used in previous studies (50 micrograms/ml) to demonstrate growth-inhibitory effects. Thus, the inhibitory effects produced by adding high concentrations of PGE1 on the initiation of DNA synthesis in Swiss 3T3 cells are not mediated by cAMP and should be regarded as nonspecific. In contrast, the mitogenic activity of PGE1 parallels its ability to increase the intracellular levels of cAMP. The findings support the proposition that a sustained increase in the level of this cyclic nucleotide acts as a mitogenic signal for confluent and quiescent Swiss 3T3 cells.


New technique for medial canthoplasty that incorporates modified v-w epicanthoplasty.
Telecanthus, which is the lateral displacement of the medial canthus, can be a congenital deformity or can occur after facial trauma. Several epicanthoplasty methods have been described, but the orbitonasal angle and appropriate shape cannot be reconstructed in Asians. We solved this problem by using a dog-ear effect. This article describes a new design for epicanthoplasty and its results.


[Imputing missing data in public health: general concepts and application to dichotomous variables].
The presence of missing data in collected variables is common in health surveys, but the subsequent imputation thereof at the time of analysis is not. Working with imputed data may have certain benefits regarding the precision of the estimators and the unbiased identification of associations between variables. The imputation process is probably still little understood by many non-statisticians, who view this process as highly complex and with an uncertain goal. To clarify these questions, this note aims to provide a straightforward, non-exhaustive overview of the imputation process to enable public health researchers ascertain its strengths. All this in the context of dichotomous variables which are commonplace in public health. To illustrate these concepts, an example in which missing data is handled by means of simple and multiple imputation is introduced.


Prednisolone absorption in coeliac disease.
The pharmacokinetic disposition of prednisolone was studied following oral administration (10 mg) to eight patients with untreated coeliac disease of mild or moderate severity, seven coeliac patients on a strict gluten-free diet and ten normal subjects. No significant differences were shown in the peak prednisolone level, the time of the peak level, the area under the concentration versus time plot, the plasma half-life and the 24 h urinary recovery of prednisolone in the three subject groups. There was however considerable variability within each group. It is concluded that the presence of coeliac disease does not significantly alter the absorption or elimination of prednisolone.


Differential Serodiagnostics of Latent Stages of Syphilis Based on Measuring IgG and IgM Levels towards Extended Panel of Recombinant Antigens of T. pallidum.
Immunochips containing 12 recombinant antigens of T. pallidum (Тр15, Тр17, Тр47, TmpA, Тр0163, Тр0277, Тр0319, Тр0453, Тр0684, Тр0965, Тр0971, and Тр1038) were prepared to assay for IgG and IgM in serum samples (n=68) of healthy individuals and patients with the latent stages of syphilis. The linear discriminant analysis of detected IgG and IgM differentiated three groups of serum samples as 1) early latent syphilis; 2) seroresistant early latent syphilis; and 3) late latent syphilis with overall differentiation potency of 95.6% (88.9-100%). The samples of all syphilis patients were differentiated from the samples of healthy individuals with 100% specificity.


Limited access to a dietary fat option affects ingestive behavior but not body composition in male rats.
Restricting access to high-fat foods is a common strategy utilized to promote health. This strategy may contribute to episodes of overconsumption, however, when the restricted foods subsequently become available. The present study utilized a rat feeding procedure to determine if restricting access to an optional source of dietary fat would increase later consumption of that food under nonenergy-deprived conditions. Five groups of male Sprague-Dawley rats were used, all of which had continuous access to a standard rodent diet and water. The control group had no access to shortening. The low-restriction group had 2-h access to shortening every day. The high-restriction group had 2-h access to shortening on Monday, Wednesday, and Friday. Two additional groups were switched between the high and low conditions. Two-hour and 24-h food intakes were measured every day for 6 weeks. At the end of the study rats were sacrificed and carcass composition determined. As access to the shortening decreased, consumption during the 2-h access period increased. Rats compensated for the increased shortening consumption by decreasing intake of the standard diet. Thus, cumulative energy consumption did not differ among the groups. When switched between the high and low conditions, rats rapidly adjusted to the change in shortening availability. There were no effects of access schedule on carcass composition. These results indicate that restricting access to an optional high-fat food, even under nonenergy-deprived conditions, can promote significant increases in the consumption of that food when it subsequently becomes available.


A nomogram for predicting overall survival in patients with endometrial carcinoma: A SEER-based study.
To construct and validate a nomogram for patients with endometrial carcinoma to predict the 3- and 5-year overall survival (OS) based on the Surveillance, Epidemiology, and End Results (SEER) database. Demographic and clinical pathologic characteristics of patients with endometrial carcinoma diagnosed between 1973 and 2015 were extracted from the SEER database. Univariate and multivariate Cox analyses were carried out to identify the independent characteristics and further included into the construction of a nomogram. Finally, concordance index and calibration curves were used to validate the nomogram. A total of 49 844 patients were enrolled into our analysis. The results of univariate Cox analysis showed that age, race, marital status, FIGO Stage, grade, and metastatic status to bone, brain, lung, or liver were significant factors. Multivariate Cox analysis was performed and it confirmed all factors as independent variables. Next, a nomogram was constructed using these independent variables in prediction of the 3- and 5-year OS. Furthermore, results with concordance indices (0.852 in training set and 0.861 in validation set) and calibration curves closer to ideal curves indicated the accurate predictive ability of this nomogram. The individualized nomogram demonstrated a good ability in prognostic prediction for patients with endometrial carcinoma.


A mutation in the interferon regulatory element of HBV may influence the response of interferon treatment in chronic hepatitis B patients.
A functional interferon regulatory element (IRE) has been found in the EnhI/X promoter region of hepatitis B virus (HBV) genome. The purpose of this study is to compare the gene order of responder and non-responder to interferon therapy in patients with chronic hepatitis B (CHB), so as to evaluate the relationship between IRE mutation and the response to interferon treatment for CHB patients. Synthetic therapeutic effect is divided into complete response (CR), partial response (PR) and non-response (NR). Among the 62 cases included in this study, 40 cases (64.5%) were in the response group (CR and PR) and 22 (35.5%) cases were in the NR group. Wild type sequence of HBV IRE TTTCACTTTC were found in 35 cases (56.5%), and five different IRE gene sequences. included TTTtACTTTC, TTTCAtTTTC, TTTtAtTTTC, TTTtACTTTt and cTTtACcTTC, were found in 22 cases (35.5%), 1 case (1.6%), 1 case (1.6%), 2 cases (3.2%) and 1 case (1.6%) respectively. There were 41.9%cases (26/62) with forth base C→T mutation, consisted of 32.5% (13/40) cases in response group and 59.1% (13/22) cases in NR group. Among the 35 cases with IRE sequences, there were 67.5% (27/40) cases in response group and 36.4% (8/22) in NR group, and the difference in IRE sequences between two groups was statistic significantly (P = 0.027). The result suggested that there is likely relationship between the forth base mutation (C→T) of IRE region and the response of HBV to Interferon therapy, and this mutation may partially decrease the inhibition effect of interferon on HBV. The forth base C→T mutation in IRE element of HBV may partially influence the response of Interferon treatment in CHB patients.


Cyclic variation in fetal heart rate and sympathetic activity.
The effects of alpha- and beta-adrenergic blockade on electrocortical activity-related cyclic variability in fetal heart rate and mean arterial pressure were investigated in eight fetal lambs between 119 and 138 days of gestation. In the absence of adrenergic blockade, fetal heart rate during high-voltage slow activity was significantly higher than that during low-voltage fast activity. Propranolol (2.0 mg/hr) produced a decrease in fetal heart rate, but the decrease was only statistically significant during high-voltage slow activity. Phentolamine (5.0 mg/hr) induced a significant increase in fetal heart rate with a small but statistically significant decrease in mean arterial pressure. The cyclic variability in fetal heart rate between low-voltage fast activity and high-voltage slow activity was abolished by propranolol and enhanced by phentolamine. These results indicate that the cyclic variability in the fetal heart rate associated with electrocortical activity can be accounted for by cyclic fluctuation in sympathetic activity.


Stroke and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Management Across Kidney Disease Stages.
Cerebrovascular disease and stroke are very common at all stages of chronic kidney disease (CKD), likely representing both shared risk factors as well as synergy among risk factors. More subtle ischemic brain lesions may be particularly common in the CKD population, with subtle manifestations including cognitive impairment. For individuals with nondialysis CKD, the prevention, approach to, diagnosis, and management of stroke is similar to the general, non-CKD population. For individuals with end-stage renal disease, far less is known regarding strategies to prevent stroke. Stroke prophylaxis using warfarin in dialysis patients with atrial fibrillation in particular remains of uncertain benefit. End-stage renal disease patients can be managed aggressively in the setting of acute stroke. Outcomes after stroke at all stages of CKD are poor, and improving these outcomes should be the subject of future clinical trials.


THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.
Characterization of previously described intraflagellar transport (IFT) mouse mutants has led to the proposition that normal primary cilia are required for mammalian cells to respond to the sonic hedgehog (SHH) signal. Here we describe an N-ethyl-N-nitrosourea-induced mutant mouse, alien (aln), which has abnormal primary cilia and shows overactivation of the SHH pathway. The aln locus encodes a novel protein, THM1 (tetratricopeptide repeat-containing hedgehog modulator-1), which localizes to cilia. aln-mutant cilia have bulb-like structures at their tips in which IFT proteins (such as IFT88) are sequestered, characteristic of Chlamydomonas reinhardtii and Caenorhabditis elegans retrograde IFT mutants. RNA-interference knockdown of Ttc21b (which we call Thm1 and which encodes THM1) in mouse inner medullary collecting duct cells expressing an IFT88-enhanced yellow fluorescent protein fusion recapitulated the aln-mutant cilial phenotype, and live imaging of these cells revealed impaired retrograde IFT. In contrast to previously described IFT mutants, Smoothened and full-length glioblastoma (GLI) proteins localize to aln-mutant cilia. We hypothesize that the aln retrograde IFT defect causes sequestration of IFT proteins in aln-mutant cilia and leads to the overactivated SHH signaling phenotype. Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in SHH signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event.


Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study.
To determine the genetic and clinical features of resistance to thyroid hormone in a study from a single institution. Prospective, controlled study. National Institutes of Health. 104 patients with resistance to thyroid hormone from 42 kindreds and 114 unaffected relatives sharing the patients' environmental and genetic backgrounds. Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10). Assessment of tissue-specific compensation for resistance. Inheritance was autosomal dominant in 22 families, sporadic in 14 families, and unknown in 6 families. We found mutations in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 were in exon 10 of the TR beta gene. In persons with resistance to thyroid hormone, we measured the increased incidence of goiter (65%), attention-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speech impediment (35%), and short stature (18%). We also described new clinical features, such as frequent ear, nose, and throat infections (56%); low weight-for-height in children (32%); hearing loss (21%); and cardiac abnormalities (18%). Genotype, age, whether the mother had resistance to thyroid hormone, and sex influenced the phenotype. Tissue resistance varied from kindred to kindred and involved, in decreasing order, the pituitary gland, the brain, the bone, the liver, and the heart. This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.


Efficiency calibration and self-attenuation correction in radioxenon measurement using β-γ coincidence method.
Measurement of the four radioxenon isotopes, namely 131mXe, 133mXe, 133Xe, and 135Xe, play a key role in underground nuclear test monitoring for ensuring compliance with the Comprehensive Nuclear-Test-Ban Treaty (CTBT). To improve detection sensitivity, a β-γ coincidence technique is commonly used. Due to the presence of the gas matrix, such as stable xenon, nitrogen, helium, the self-attenuation effects should be taken into account when measuring different types of sample. In order to improve the accuracy of the measurement, the detection efficiencies of X-rays and γ-rays were derived by using a simulation gas calibration source with low density of sponge matrix. The detection efficiencies of β-particles and conversion electrons (CEs) were calibrated by measuring radioxenon sample. The self-attenuation correction factors of X-rays and γ-rays were determined by Geant4 simulation method. The self-attenuation correction factors of β-particles and CEs were provided by measuring the radioxenon samples with different volumes of xenon, nitrogen and helium.


The Effect of Chronic and End-Stage Renal Disease on Long-Term Outcomes after Infrainguinal Bypass.
Patients undergoing infrainguinal bypass for chronic limb threatening ischemia (CLTI) with renal dysfunction are at an increased risk for perioperative and long-term morbidity and mortality. Our goal was to examine perioperative and 3-year outcomes after lower extremity bypass for CLTI stratified by kidney function. A retrospective, single-center analysis of lower extremity bypass for CLTI was performed between 2008 and 2019. Kidney function was categorized as normal (estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2), chronic kidney disease (CKD) (eGFR 15-59 mL/min/1.73 m2), and end-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m2). Kaplan-Meier and multivariable analysis were performed. There were 221 infrainguinal bypasses performed for CLTI. Patients were classified by renal function as normal (59.7%), CKD (24.4%), and ESRD (15.8%). Average age was 66 years and 65% were male. Overall, 77% had tissue loss with 9%, 45%, 24%, and 22% being Wound, Ischemia, and foot Infection stages 1-4, respectively. The majority (58%) of bypass targets was infrapopliteal and 58% used ipsilateral greater saphenous vein. The 90-day mortality and readmission rates were 2.7% and 49.8%, respectively. ESRD, compared to CKD and normal renal function, respectively, had the highest 90-day mortality (11.4% vs. 1.9% vs. 0.8%, P = 0.002) and 90-day readmission (69% vs. 55% vs. 43%, P = 0.017). On multivariable analysis, ESRD, but not CKD, was associated with higher 90-day mortality (odds ratio (OR) 16.9, 95% confidence interval (CI) 1.83-156.6, P = 0.013) and 90-day readmission (OR 3.02, 95% CI 1.2-7.58, P = 0.019). Kaplan-Meier 3-year analysis showed no difference between groups for primary patency or major amputation; however, ESRD, compared to CKD and normal renal function, respectively, had worse primary-assisted patency (60% vs. 76% vs. 84%, P = 0.03) and survival (72% vs. 96% vs. 94%, P = 0.001). On multivariable analysis, ESRD and CKD were not associated with 3-year primary patency loss/death, but ESRD was associated with higher primary-assisted patency loss (hazard ratio (HR) 2.61, 95% CI 1.23-5.53, P = 0.012). ESRD and CKD were not associated with 3-year major amputation/death. ESRD was associated with higher 3-year mortality (HR 4.95, 95% CI 1.52-16.2, P = 0.008) while CKD was not. ESRD, but not CKD, was associated with higher perioperative and long-term mortality after lower extremity bypass for CLTI. Although ESRD was associated with lower long-term primary-assisted patency, there were no differences in loss of primary patency or major amputation.


Atypical and typical neuroleptics in acute schizophrenia and related delusional disorders. Drug choice, switching and outcome under naturalistic treatment conditions.
Atypical neuroleptics have improved drug treatment in schizophrenia. However, their use varies greatly between countries and continents. Recent metaanalyses have deemphasized the range and magnitude of their superiority compared to typical neuroleptics. Aims of the present study were to contribute effectiveness data to this discussion. In 725 inpatients with ICD-10 diagnoses F20, 22-25 from four German psychiatric inpatient units acute neuroleptic treatment and outcome were analyzed under naturalistic conditions. Treatment strategies were stratified post hoc to answer the question, which proportion - and which kind - of patients are primarily given atypicals or typicals, for how long, at which rate and when the atypical/typical drugs are switched to typical/atypical drugs, and what the respective outcomes are. As the results demonstrate, atypicals were administered one time during inpatient treatment in nearly 48% of the patients, however as first choice drugs in only 15% of this population. Treatment change occurred in 28% after 5-6 weeks irrespective of the first drug choice. Outcome differences were, if at all, only modest and not systematically biased towards a single strategy. In conclusion, frequency of inpatient treatment with atypical neuroleptics corresponds to pharmaco-epidemiological data in Europe, but is still lower than in the US. Contrary to contemporary guideline recommendations atypical neuroleptics under routine inpatient treatment conditions were scarcely administered as first choice treatment, and acute clinical outcome is comparable to that under treatment with typical neuroleptics. Reasons and implications of these findings considering the methodological limitations are discussed.


The Pain Medical Home: A Patient-Centered Medical Home Model of Care for Patients with Chronic Pain.
Chronic pain affects an estimated 100 million people a year in the United States and costs society anywhere from $560 to $635 billion annually. The patient-centered medical home and the patient-centered medical home-neighbor models of care have been advocated to improve patient outcomes. These models of care advocate improved coordination of care within the primary care and specialty care setting. The authors present the patient-centered medical home model of care and suggest how this model of care might be used to improve patient outcomes for patients with chronic pain.


[Rib fracture after postoperative tangential irradiation in breast cancer].
Incidence of rib fracture was analyzed for 118 postoperated breast cancer patients who were tangentially irradiated at the Department of Radiology, Kyushu University, from 1961 to 1976 and followed more than 5 years. Rib fracture was observed in 5% and 50% of cases treated with total radiation doses of 32.5 Gy and 52.5 Gy respectively.


Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51).
The present analysis reports on the pre-specified subgroup of ST-elevation myocardial infarction (STEMI) patients, in whom anticoagulant therapy has been of particular interest. In ATLAS ACS-2-TIMI-51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51), rivaroxaban reduced cardiovascular events across the spectrum of acute coronary syndrome (ACS). Seven thousand eight hundred seventeen patients in ATLAS ACS-2-TIMI 51 presented with a STEMI. After being stabilized (1 to 7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for intention-to-treat (ITT) and modified ITT (mITT) analyses. Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (ITT: 8.4% vs. 10.6%, hazards ratio [HR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.97, p = 0.019; mITT: 8.3% vs. 9.7%, HR: 0.85, 95% CI: 0.70 to 1.03, p = 0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, p = 0.042) and was evident in analyses that included events while patients received background dual antiplatelet therapies (ITT: 7.9% vs. 11.9%, p = 0.010; mITT: 7.7% vs. 10.1%, p = 0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, p = 0.006; mITT: 2.2% vs. 3.9%, p = 0.006), which was not seen with 5 mg of rivaroxaban. Rivaroxaban versus placebo increased non-coronary artery bypass grafting Thrombolysis In Myocardial Infarction major bleeding (2.2% vs. 0.6%, p < 0.001) and intracranial hemorrhage (0.6% vs. 0.1%, p = 0.015) without a significant increase in fatal bleeding (0.2% vs. 0.1%, p = 0.51). In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).


Scar-free cutaneous wound healing in the leopard gecko, Eublepharis macularius.
Cutaneous wounds heal with two possible outcomes: scarification or near-perfect integumentary restoration. Whereas scar formation has been intensively investigated, less is known about the tissue-level events characterising wounds that spontaneously heal scar-free, particularly in non-foetal amniotes. Here, a spatiotemporal investigation of scar-free cutaneous wound healing following full-thickness excisional biopsies to the tail and body of leopard geckos (Eublepharis macularius) is provided. All injuries healed without scarring. Cutaneous repair involves the development of a cell-rich aggregate within the wound bed, similar to scarring wounds. Unlike scar formation, scar-free healing involves a more rapid closure of the wound epithelium, and a delay in blood vessel development and collagen deposition within the wound bed. It was found that, while granulation tissue of scarring wounds is hypervascular, scar-free wound healing conspicuously does not involve a period of exuberant blood vessel formation. In addition, during scar-free wound healing the newly formed blood vessels are typically perivascular cell-supported. Immunohistochemistry revealed widespread expression of both the pro-angiogenic factor vascular endothelial growth factor A and the anti-angiogenic factor thrombospondin-1 within the healing wound. It was found that scar-free wound healing is an intrinsic property of leopard gecko integument, and involves a modulation of the cutaneous scar repair program. This proportional revascularisation is an important factor in scar-free wound healing.


Increasing retirement ages in Denmark: Do changes in gender, education, employment status and health matter?
Recent studies report significant increases in retirement ages over the past two to three decades in most countries in the Organization for Economic Co-operation and Development-increases that research has attributed mainly to changes in the legislative frameworks for retirement in these countries. Using unique data from the Danish Longitudinal Study of Ageing, this study investigates whether and, if so to what extent, changes to the workforce in terms of gender, education, employment status (employed or self-employed) and health contribute to explaining differences in retirement ages between the cohorts born in 1935 and 1950. The retirement window of these cohorts stretches from the early 1990s to the late 2010s-a period characterized by substantial changes to workforce. On average, retirement ages increased by two years from the 1935 cohort to the 1950 cohort. However, due to changes in the investigated factors having offsetting effects, the net effect of such changes on retirement ages was minor. Thus, while increasing levels of education and better health among older workers contributed to increasing retirement ages, increasing female labour force participation and fewer self-employed workers had the opposite effect. In absolute terms, the total compositional and behavioural influence on retirement ages of changes in terms of employment status (- 0.35 years) was almost as large as the total changes in terms of education (0.44 years). Thus, future studies investigating long-term changes in retirement ages would benefit from including changes in employment status (self-employed or wage earner) as an explanatory factor.


Silencing MicroRNA-155 Attenuates Cardiac Injury and Dysfunction in Viral Myocarditis via Promotion of M2 Phenotype Polarization of Macrophages.
Macrophage infiltration is a hallmark feature of viral myocarditis. As studies have shown that microRNA-155 regulates the differentiation of macrophages, we aimed to investigate the role of microRNA-155 in VM. We report that silencing microRNA-155 protects mice from coxsackievirus B3 induced myocarditis. We found that microRNA-155 expression was upregulated and localized primarily in heart-infiltrating macrophages and CD4(+) T lymphocytes during acute myocarditis. In contrast with wildtype (WT) mice, microRNA-155(-/-) mice developed attenuated viral myocarditis, which was characterized by decreased cardiac inflammation and decreased intracardiac CD45(+) leukocytes. Hearts of microRNA-155(-/-) mice expressed decreased levels of the IFN-γ and increased levels of the cytokines IL-4 and IL-13. Although total CD4(+) and regulatory T cells were unchanged in miR-155(-/-) spleen proportionally, the activation of T cells and CD4(+) T cell proliferation in miR-155(-/-) mice were significantly decreased. Beyond the acute phase, microRNA-15(5-/-) mice had reduced mortality and improved cardiac function during 5 weeks of follow-up. Moreover, silencing microRNA-155 led to increased levels of alternatively-activated macrophages (M2) and decreased levels of classically-activated macrophages (M1) in the heart. Combined, our studies suggest that microRNA-155 confers susceptibility to viral myocarditis by affecting macrophage polarization, and thus may be a potential therapeutic target for viral myocarditis.


[Cardiovascular risk factors in chronic obstructive pulmonary disease: results of the ARCE study].
Cardiovascular disease is a common cause of death in patients with chronic obstructive pulmonary disease (COPD). It is not clear whether the high cardiovascular comorbidity is due to an increase in traditional risk factors or whether, in contrast, COPD can be considered an independent risk factor. The aim of this study was to analyze the prevalence of risk factors and cardiovascular comorbidity in a community-based population treated for COPD. This was a concurrent multicenter, cross-sectional study that included 572 patients with confirmed diagnosis of COPD. Information on cardiovascular risk factors and comorbidity was collected by extracting data from the medical records of the participating center. The mean (SD) forced expiratory volume in 1 second (FEV1) was 53.7% (16.85%) of predicted and the ratio of FEV1 to forced vital capacity was 57.9% (10.9%). Hypertension was reported in 53%, obesity in 27%, dyslipidemia in 26%, and diabetes in 23% of the patients. The prevalence of risk factors was not related to disease severity, but there was a trend towards an association with age. In the study group, 16.4% had ischemic heart disease, 7% cerebrovascular disease, and 17% peripheral vascular disease. Cardiovascular disease was not associated with COPD severity, but such an association was reported for age and traditional risk factors. Cardiovascular risk factors are highly prevalent in patients with COPD. The prevalence of cardiovascular and cerebrovascular disease exceeds that reported in the general population. No relationship was found between the severity of airflow obstruction and the presence of cardiovascular comorbidity.


A Synthesis of Dihydro Eurotiumide B via a Tandem Butenolide Annulation/Reductive Thiolation Reaction.
Dihydro eurotiumide B was prepared from a 5-phenylthiobutenolide via a tandem annulation/reductive thiolation reaction.


Impact of COVID- 19 pandemic on antidepressants consumptions by wastewater analysis in Turkey.
The COVID-19 pandemic has been a major challenge worldwide, forcing countries to take restrictive measures beyond conventional methods in their fight against the spread of the disease. Followingly, many studies have been conducted on the effects of these measures on mental health. Wastewater-based epidemiology (WBE) was used in this study to monitor and estimate changes in antidepressant use under normal conditions (2019) and COVID-19 pandemic conditions (2020). Likewise, this study utilized wastewater-based epidemiology (WBE) to monitor and assess changing trends from the pre-pandemic period (2019) to COVID-19 pandemic conditions in antidepressant use (2020). Wastewater samples were collected from 11 cities in Turkey throughout six sampling periods covering the pre-pandemic and during-pandemic periods (June 2019-December 2020). Then, samples were analyzed via LC-MS/MS method. As a result, we observed that venlafaxine was the drug with the highest concentration (mean ± SD: 103.6 ± 112.1 mg/1000p/day). Moreover, city number 6 presented the highest venlafaxine use and the most dramatic increase during the pandemic period. Finally, this study revealed the potential of WBE to estimate the changing trends in mental health during the ongoing pandemic.


Endogenous oscillations in pathways of energy transduction as related to circadian rhythmicity and photoperiodic control.
Evidence is presented for endogenous rhythmicity in energy transducing sequences of cellular metabolism which result in a circadian rhythm in adenylate "energy charge" and redox state (NADPH/NADP). From phase dependent photocontrol of enzymatic activity and pyridine nucleotide pool-size levels it is concluded that light - via photoreceptor(s) of photoperiodic control - modulates energy flow under conditions where overall energy transduction displays a circadian rhythm. The results are discussed in relation to temporal organization of development in general.


Radiological assessment subjected to outdoor radon and thoron concentrations and terrestrial gamma radiation measurements in Perak Malaysia.
The concentrations of radon, thoron and terrestrial gamma radiation were measured to evaluate the outdoor effective dose. The outdoor radon activity concentration ranged from 5.79 to 5110 ± 46.36 Bq m-3, with a mean of 320.03 Bq m-3 which is higher than the EPA level of 14.8 Bq m-3. The range of the thoron activity concentration outdoor was from 0.00 to 4226.7 ± 58.5 Bq m-3, with a mean of 226.1 Bq m-3 which was above the UNSCEAR recommended level of 10 Bq m-3. The terrestrial gamma radiation dose rates range was from 98.31 to 3769.71 nGy h-1 with a mean of 446.27 nGy h-1. The effective dose contribution from radon exposures in the study was estimated to be 3.2 ± 0.5 mSv y-1 is about 84% total annual effective dose received by the population in those areas. The estimated thoron and gamma dose contributions (15%, and 1% respectively) were not significant. The outdoor doses for thoron and gamma were lower than the ICRP (2007) value of 1 mSv. The total annual outdoor effective dose with an occupancy factor of 1825 h (5 h day-1) was estimated to be within the range of 0.30-551.41 ± 0.65 mSv, with a mean of 3.75 mSv which is a little higher than the world average of 2.4 mSv.


Idarucizumab for Reversal of Dabigatran: Single-Center Real-World Experience.
Idarucizumab is used to reverse the effects of dabigatran. Information on the use of idarucizumab in the clinical setting remains very limited. The objective of this study was to describe clinical experience with idarucizumab in a large medical teaching center in the USA. Patients who received idarucizumab to reverse the effects of dabigatran between 1 January 2016 and 30 June 2018 were studied. In patients with major bleeding, the efficacy of idarucizumab was assessed using criteria of the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee. The course of treatment and clinical outcomes in patients who received idarucizumab for emergency surgery or procedures are described. In total, 13 patients received idarucizumab for atrial fibrillation during the study period. Their mean age was 77.5 ± 7.1 years, and 12 (92.3%) were men. Idarucizumab was used in 11 patients for major bleeding events and in two patients for emergency surgery or procedures. Intracranial hemorrhage (n = 6) and gastrointestinal bleed (n = 2) were the most common types of bleeding. Clinical hemostasis was achieved in 8 of 11 (72.7%) patients with major bleeding. One patient with acute kidney injury needed two doses of the reversal agent to achieve hemostasis. One patient underwent open heart surgery and developed postoperative hemorrhage despite receiving idarucizumab. None of the patients experienced thrombotic complications or side effects that could be attributed to idarucizumab. Real-world experience in a US hospital with the use of idarucizumab in emergency situations requiring the reversal of the effects of dabigatran is described. Idarucizumab represents an exciting new antidote for dabigatran, but clinical efficacy and cost-effectiveness data remain lacking.


Autoradiographic localization of binding sites for 2-[125I]iodomelatonin in the pars tuberalis of the western spotted skunk (Spilogale putorius latifrons).
Pineal melatonin secretion mediates photoperiodic regulation of implantation of blastocysts in the female western spotted skunk. Autoradiography studies demonstrated that high affinity 2-[125I]iodomelatonin binding sites are present in the pars tuberalis but not in any other hypophyseal region or in the hypothalamus or thalamus of this species. This restricted localization of 2-[125I]iodomelatonin binding, which was characteristic of spotted skunks sacrificed at various times during their annual reproductive cycles, suggests that the pars tuberalis mediates photoperiodic responses in this species.


Conditioned and unconditioned fear organized in the periaqueductal gray are differentially sensitive to injections of muscimol into amygdaloid nuclei.
The lateral and basolateral nuclei of the amygdala (LaA and BLA, respectively) serve as a filter for unconditioned and conditioned aversive information that ascends to higher structures from the brainstem, whereas the central nucleus of the amygdala (CeA) is considered to be the main output for the defense reaction. It has been shown that the dorsal periaqueductal gray (dPAG) is activated by threatening stimuli and has important functional links with the amygdala through two-way anatomical connections. In this work, we examined the influence of chemical inactivation of these nuclei of amygdala on the freezing and escape responses induced by electrical stimulation through electrodes implanted in the dPAG of Wistar rats. Each rat also bore a cannula implanted in the LaA, BLA or CeA for injections of muscimol (0.5 microg/0.5 microL) or its vehicle. The duration of freezing behavior that outlasts electrical stimulation of the dPAG was also measured. On the following day, these animals were submitted to a contextual fear-conditioning using foot shocks as unconditioned stimulus. Conditioned freezing to contextual cues previously associated with foot shocks was also inhibited by injections of muscimol into these amygdaloid nuclei. The contextual conditioned freezing behavior is generated in the neural circuits of conditioned fear in the amygdala. The data obtained also show that injections of muscimol into the three amygdaloid nuclei did not change the aversive threshold of freezing, but disrupted the dPAG post-stimulation freezing. Previous findings that the latter freezing results directly from dPAG stimulation and that it is not sensitive to a context shift suggest that it is unconditioned in nature. Thus, the amygdala can affect some, but not all, aspects of unconditioned freezing. Post-stimulation freezing may reflect the process of transferring aversive information from dPAG to higher brain structures.


Fluorous oxime palladacycle: a precatalyst for carbon-carbon coupling reactions in aqueous and organic medium.
To facilitate precatalyst recovery and reuse, we have developed a fluorous, oxime-based palladacycle 1 and demonstrated that it is a very efficient and versatile precatalyst for a wide range of carbon-carbon bond formation reactions (Suzuki-Miyaura, Sonogashira, Stille, Heck, Glaser-type, and Kumada) in either aqueous or organic medium under microwave irradiation. Palladacycle 1 could be recovered through F-SPE in various coupling reactions with recovery ranging from 84 to 95% for the first cycle. Inductively coupled plasma optical emission spectrometry (ICP-OES) analyses of the Pd content in the crude product from each class of transformation indicated extremely low levels of leaching and the palladacycle could be reused four to five times without significant loss of activity.


Preclinical evaluation from in-silico to in-vivo study of polyherbal microsponge sunscreen gel.
Electromagnetic spectrum of the UV region predominantly becomes the reason for skin's detrimental effects that give the genesis of innumerable skin ailments; because of this reason, the sunscreen products are required before condition in day to day lifestyle; products such as moisturizers, lotions, creams, shampoos, and other hair and skin preparations are accessible and accompanied by sunscreen properties, but they do not provide extended effect, also causes side effects due to harsh chemicals. The present study focuses on the effects of polyherbal extracts containing Microsponge gel for the protection of skin from ultraviolet rays. In the present research, already prepared Microsponge gel through quasi-emulsion solvent diffusion (QESD) technique was used for the HPLC, in-silico, in-vitro antioxidant activity, and in-vivo study. AdmetSAR software tool was utilized for the in-silico study, whereas for the in-vivo study, UV radiations are given on Albino rats using solarimeter. Results shown the active constituents are non-carcinogenic and non-toxic; IC50 values show good antioxidant activity and minimal effect of UV radiations after application of the gel formulation on animal skin. The results manifest prominent effects on animal skin further test for presence of ascorbic acid level and total protein in blood further verify the efficacy of the formulation. The study consequently established a strong ground for further extensive clinical studies.


Pulmonary hypertension due to recurrent juvenile laryngeal papillomatosis.
Although pulmonary hypertension secondary to upper airway obstruction caused by adenotonsillar hyperplasia has been well described, the association between laryngeal papillomatosis and pulmonary hypertension has not previously been documented. We report three patients with pulmonary hypertension due to upper airway obstruction caused by laryngeal papillomatosis. Pulmonary hypertension can contribute to significant preoperative and postoperative morbidity and cause intraoperative complications. Preoperative diagnosis and treatment of pulmonary hypertension is therefore essential in these patients.


Neural representations of Groups and Stereotypes using fMRI repetition suppression.
Categorizing people in groups and associating them with stereotypical behavior is an integral part of human social understanding and interaction. This study investigates where knowledge on social groups and their stereotypes is represented in the brain. We presented participants with two sentences describing a group member (e.g. the police officer) performing a behavior believed to be stereotypical of the group (e.g. makes an arrest, i.e. authoritative), and asked them to rate the degree to which the behavior was typical of the group. Our critical manipulation was the repetition of this information across the two sentences: Either both the group and the stereotype implied by the behavior was repeated, only the group was repeated, only the stereotype implied by the behavior, or neither. Results showed robust suppression of hemodynamic activation from the first to second sentence in the medial prefrontal cortex in response to the repetition of the stereotype implied in the behavior, but only when groups were different. This finding suggests that the neural representation of stereotypes is located in this area, and this is in line with similar repetition suppression research showing trait representation in this area. A suppression effect for the repetition of groups was observed in the posterior cingulate cortex, regardless of whether stereotypes were repeated or not. This finding suggests that the neural representation of groups is located in this area. Because this location is unexpected, we discuss several suggestions for future research to confirm this finding.


The Phaff school of yeast ecology.
Herman Jan Phaff's legacy includes pioneering work on the yeast cell envelope and the application of molecular approaches to yeast systematics. Clearly, his interest and knowledge spanned the whole gamut of yeast biology. Yet, his most original and most heartfelt contribution was to our understanding of the position occupied by yeasts in nature. This view developed through the juxtaposition of his childhood exposure to industrial fermentations and his training in the tradition of Beijerinck's Delft School of Microbiology. Through some of Phaff's recent writings, I have attempted to formulate the themes or principles that were implicit to his ecological thinking. Six focal points emerge. (1) Yeasts in themselves are a sufficient object of study. (2) A clear idea of a yeast community cannot be obtained unless the yeast species are correctly identified. (3) Ecologically meaningful conclusions require an adequate sample size. (4) The bacteriological dictum "everything is everywhere" is a poor account of yeast distributions. (5) The habitat is the cornerstone of yeast ecology. (6) Ecology is the most exciting aspect of yeast biology.