The effect of low- and high-dose levothyroxine on the expression, protein level, and function of P-glycoprotein in mice: The effect of levothyroxine on P-gp is variable

The study was investigated the effect of different doses of levothyroxine on the mRNA expression, protein level and function of Pgp. Mice were divided into 6 groups as control, low dose levothyroxine, high dose levothyroxine, fexofenadine, low dose levothyroxine+fexofenadine and high dose levothyroxine+fexofenadine. Mice received levothyroxine at doses of 8 and 80 µg/kg daily for 21 days. Fexofenadine was administered at dose of 40 mg/kg at the 24 h following the last administration of levothyroxine. The mRNA levels and protein level of Pgp in liver and small intestine were determined by RT-PCR and western blot analysis, respectively. Plasma concentrations of fexofenadine were determined using HPLC. Levothyroxine at low and high doses caused an insignificant increase intestinal mRNA expression of mdr1a, while high dose levothyroxine+fexofenadine caused a significant increase. Levothyroxine caused a dose-dependent decrease in intestinal mRNA expression of mdr1b. In liver, levothyroxine caused a dose-dependent increase in the mRNA expression of mdr1a. Fexofenadine significantly reduced the effect of levothyroxine on mRNA expression of mdr1a in liver. Levothyroxine increased the protein level of Pgp in liver and decrease in intestines. Low dose levothyroxine significantly increased the plasma concentration of fexofenadine. The effects of levothyroxine on the mRNA expression of mdr1a and b in small intestine and liver and protein level of Pgp varied depending on the dose, tissue type, and fexofenadine administration

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Nasopharynx evaluation in children of unilateral cleft palate patients and normal with cone beam computed tomography

OBJECTIVE: This study aimed to examine the morphological characteristics of the nasopharynx in unilateral Cleft lip/palate (CL/P) children and non-cleft children using cone beam computed tomography (CBCT). METHODS: A retrospective study consisted of 54 patients, of which 27 patients were unilateral CL/P, remaining 27 patients have no CL/P. Eustachian tubes orifice (ET), Rosenmuller fossa (RF) depth, presence of pharyngeal bursa (PB), the distance of posterior nasal spine (PNS)-pharynx posterior wall were quantitatively evaluated. RESULTS: The main effect of the CL/P groups was found to be effective on RF depth-right (p < 0.001) and RF depth-left (p < 0.001). The interaction effect of gender and CL/P groups was not influential on measurements. The cleft-side main effect was found to be effective on RF depth-left (p < 0.001) and RF depth-right (p  =  0002). There was no statistically significant relationship between CL/P groups and the presence of bursa pharyngea. CONCLUSIONS: Because it is the most common site of nasopharyngeal carcinoma (NPC), the anatomy of the nasopharynx should be well known in the early diagnosis of NPC

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Spectral renormalization group theory on networks

Discrete amorphous materials are best described in terms of arbitrary networks which can be embedded in three dimensional space. Investigating the thermodynamic equilibrium as well as non-equilibrium behavior of such materials around second order phase transitions call for special techniques. We set up a renormalization group scheme by expanding an arbitrary scalar field living on the nodes of an arbitrary network, in terms of the eigenvectors of the normalized graph Laplacian. The renormalization transformation involves, as usual, the integration over the more "rapidly varying" components of the field, corresponding to eigenvectors with larger eigenvalues, and then rescaling. The critical exponents depend on the particular graph through the spectral density of the eigenvalues.Comment: 17 pages, 3 figures, presented at the Continuum Models and Discrete Systems (CMDS-12), 21-25 Feb 2011, Saha Institute of Nuclear Physics, Kolkata, Indi

Brucella bacteremia in patients with acute leukemia: a case series

<p>Abstract</p> <p>Background</p> <p>Brucellosis may cause serious infections in healthy individuals living in countries that are endemic for the infection. However, reports of brucella infections in immunocompromised hosts are relatively rare.</p> <p>Case Presentations</p> <p>Reported here are two patients with acute leukemia who developed <it>Brucella melitensis </it>bacteremia during their follow up at the Armed Forces Hospital in Riyadh. The first patient developed <it>B. melitensis </it>bacteremia during the transformation of his myelodysplasia into acute myeloid leukemia. The second patient developed <it>B. melitensis </it>bacteremia while his acute lymphoblastic leukemia was under control. Interestingly, he presented with acute cholecystitis during the brucella sepsis. Both brucella infections were associated with a marked reduction in the hematological parameters in addition to other complications. The bacteremic episodes were successfully treated with netilmicin, doxycycline and ciprofloxacin.</p> <p>Conclusion</p> <p>Brucellosis can cause systemic infections, complicated bacteremia and serious morbidity in patients with acute leukemia living in endemic areas. These infections may occur at the presentation of the leukemia or even when the leukemia is in remission. Nevertheless, the early diagnosis of brucellosis and the administration of appropriate antimicrobial therapy for sufficient duration usually improves the outcome in these immunocompromised patients.</p

Detection limits and trigger rates for ultra-high energy cosmic ray detection with the EUSO-TA ground-based fluorescence telescope

EUSO-TA is a ground-based fluorescence telescope built to validate the design of ultra-high energy cosmic ray fluorescence detectors to be operated in space with the technology developed within the Joint Exploratory Missions for Extreme Universe Space Observatory (JEM-EUSO) program. It operates at the Telescope Array (TA) site in Utah, USA. With an external trigger provided by the Black Rock Mesa fluorescence detectors of the Telescope Array experiment, with EUSO-TA we observed air-showers from ultra-high energy cosmic rays, as well as laser events from the Central Laser Facility at the TA site and from portable lasers like the JEM-EUSO Global Light System prototype. Since the Black Rock Mesa fluorescence detectors have a ∼30 times larger field of view than EUSO-TA, they allow a primary energy reconstruction based on the observation of a large part of the shower evolution, including the shower maximum, while EUSO-TA observes only a part of it, usually far away from the maximum. To estimate the detection limits of EUSO-TA in energy and distance, a method was developed to re-scale their energy, taking into account that EUSO-TA observes only a portion of the air- showers. The method was applied on simulation sets with showers with different primaries, energy, direction, and impact point on the ground, as well as taking into account the experimental environment. EUSO-TA was simulated with an internal trigger and different elevation angles and electronics. The same method was then applied also to real measurements and compared to the simulations. In addition, the method can also be used to estimate the detection limits for experiments that are operated at high altitudes and in most cases can see the maximum of the showers. This was done for EUSO-SPB1, an instrument installed on a super-pressure balloon. Finally, the expected detection rates for EUSO-TA were also assessed using the prepared simulated event sets. The rates correspond to a few detections per recording session of 30 h of observation, depending on the background level and the configuration of the detector

The Roadmap to the POEMMA mission

The Probe Of Extreme Multi-Messenger Astrophysics (POEMMA) is designed to observe ultrahigh-energy cosmic rays (UHECRs) and cosmic neutrinos from space with sensitivity over the full celestial sky. Developed as a NASA Astrophysics Probe-class mission, POEMMA consists of two identical telescopes orbiting the Earth in a loose formation designed to observe extensive air showers (EAS) via air fluorescence and Cherenkov emissions. UHECRs and UHE neutrinos above 20 EeV are observed with the stereo fluorescence technique, while tau neutrinos above 20 PeV are observed via the optical Cherenkov signals produced by up-going EAS generated by the decay of Earth-emerging tau-leptons. The POEMMA satellites are designed to quickly re-orientate to follow up transient cosmic neutrino candidate sources and obtain unparalleled neutrino flux sensitivity. Both observation techniques and the instrument design are being validated by current and upcoming missions, such as Mini-EUSO and EUSO-SPB as part of the JEM-EUSO program, and the Terzina instrument onboard the NUSES SmallSat mission. We discuss the POEMMA science performance and the current roadmap to the POEMMA mission

Prospects for Cross-correlations of UHECR Events with Astrophysical Sources with Upcoming Space-based Experiments

Ultra-high energy cosmic rays (UHECRs) are the messengers of the most extreme physics in the cosmos; however, efforts to identify their origins have thus far been thwarted by the fact that they don’t point back to their sources. Using statistical studies cross-correlating UHECR arrival directions with astrophysical catalogs, the ground-based Pierre Auger Observatory has reported hints of a correlation with nearby starburst galaxies, as well as lower-significance correlations with other classes of astrophysical sources. Space-based UHECR experiments, such as POEMMA and ZAP, will monitor large interaction volumes on the Earth or the Moon. Within a few years of mission operation time, both missions will achieve unprecedented exposures at energies above 40 EeV across the entire sky. We present studies of the cross-correlation between UHECR event arrival directions and astrophysical catalogs as motivated by expectations for the detector performance for POEMMA and ZAP. We find that both POEMMA and ZAP will achieve 5σ discovery reach for many plausible astrophysical scenarios

SecA, a remarkable nanomachine

Biological cells harbor a variety of molecular machines that carry out mechanical work at the nanoscale. One of these nanomachines is the bacterial motor protein SecA which translocates secretory proteins through the protein-conducting membrane channel SecYEG. SecA converts chemically stored energy in the form of ATP into a mechanical force to drive polypeptide transport through SecYEG and across the cytoplasmic membrane. In order to accommodate a translocating polypeptide chain and to release transmembrane segments of membrane proteins into the lipid bilayer, SecYEG needs to open its central channel and the lateral gate. Recent crystal structures provide a detailed insight into the rearrangements required for channel opening. Here, we review our current understanding of the mode of operation of the SecA motor protein in concert with the dynamic SecYEG channel. We conclude with a new model for SecA-mediated protein translocation that unifies previous conflicting data