The use of N-t-butyl hydroxylamine for radioprotection in cultured cells and mice.
Exposure of cells to ionizing radiation leads to formation of reactive oxygen species (ROS) that are associated with radiation-induced cytotoxicity. Therefore, compounds that scavenge ROS may confer radioprotective effects. Recently, it has been shown that the decomposition product of the spin-trapping agent alpha-phenyl-N-t-butylnitrone (PBN), N-t-butyl hydroxylamine (NtBHA), mimics PBN and is much more potent in delaying ROS-associated senescence. We investigated the protective role of NtBHA against ionizing radiation in U937 cells and mice. Viability and cellular oxidative damage reflected by lipid peroxidation, oxidative DNA damage and protein oxidation were significantly lower in the cells treated with NtBHA when the cells were exposed to ionizing radiation. The modulation of cellular redox status was more pronounced in control cells compared with NtBHA-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of ROS and the reduction of ATP production was significantly higher in control cells compared with NtBHA-treated cells. NtBHA administration before irradiation at 5 mg/kg daily for 2 weeks provided substantial protection against killing and oxidative damage to mice exposed to whole-body irradiation. These data indicate that NtBHA may have great application potential as a new class of in vivo, non-sulfur containing radiation protector.


Risk-benefit analysis of mineral intakes: case studies on copper and iron.
Dietary reference values for essential trace elements are designed to meet requirements with minimal risk of deficiency and toxicity. Risk-benefit analysis requires data on habitual dietary intakes, an estimate of variation and effects of deficiency and excess on health. For some nutrients, the range between the upper and lower limits may be extremely narrow and even overlap, which creates difficulties when setting safety margins. A new approach for estimating optimal intakes, taking into account several health biomarkers, has been developed and applied to selenium, but at present there are insufficient data to extend this technique to other micronutrients. The existing methods for deriving reference values for Cu and Fe are described. For Cu, there are no sensitive biomarkers of status or health relating to marginal deficiency or toxicity, despite the well-characterised genetic disorders of Menkes and Wilson's disease which, if untreated, lead to lethal deficiency and overload, respectively. For Fe, the wide variation in bioavailability confounds the relationship between intake and status and complicates risk-benefit analysis. As with Cu, health effects associated with deficiency or toxicity are not easy to quantify, therefore status is the most accessible variable for risk-benefit analysis. Serum ferritin reflects Fe stores but is affected by infection/inflammation, and therefore additional biomarkers are generally employed to measure and assess Fe status. Characterising the relationship between health and dietary intake is problematic for both these trace elements due to the confounding effects of bioavailability, inadequate biomarkers of status and a lack of sensitive and specific biomarkers for health outcomes.


Hepatic nuclear factor 1 (HNF1) shows a wider distribution than products of its known target genes in developing mouse.
Hepatic nuclear factor 1 (HNF1) is a highly diverged homeoprotein that is crucial for transcription of many liver-specific genes including albumin. In particular, a minimal promoter, consisting of an HNF1-binding-site and a TATA box, is highly active only in hepatoma cell lines. The expression of the HNF1 and albumin genes has been examined in mouse embryos by in situ hybridization. At 10.5 days of gestation, the HNF1 mRNA was detected in both the hepatic primordia and visceral endoderm of the yolk sac whereas the albumin transcript was present only in the nascent liver. At later stages of development, HNF1 was detected in liver, in the epithelial cells of most of the digestive tract and in the cortex of the kidney, whereas albumin was again found only in the liver. The presence of HNF1 protein in adult kidney was demonstrated by immunodetection in gel-retardation assays and western blot analysis. These experiments show that, even though the HNF1 homeo-protein is essential for expression of many liver-specific genes, it cannot, by itself, force high expression levels of these genes, in non-hepatic tissues.


The shape and size of hydroxyapatite particles dictate inflammatory responses following implantation.
The extent of regeneration following biomaterial implantation is dependent on the microenvironment surrounding the implant. Since implant composition can have a profound effect on inflammation, it is essential to understand this process as a non-resolving inflammatory response can lead to fibrous encapsulation and insufficient integration. Incorporation of particulates into implants confers structural and functional benefits, thus optimizing particulate characteristics to enhance immune mediated efficacy is important. We investigated the relationship between the nature of hydroxyapatite (HA) particles and the innate immune response, focusing on how particle size (0.1 µm, 5 µm, 20 µm, 100 µm) and morphology (needle-shaped/spherical; smooth/rough surface) modulates inflammatory responses. We observed a shape and size-dependent activation of the NLRP3 inflammasome and IL-1β secretion; while needle-shaped and smaller HA particles significantly enhanced cytokine secretion, larger particles did not. Moreover, HA particle characteristics profoundly influenced patterns of innate immune cell recruitment and cytokine production following injection. While small, needle-shaped particles induced a strong inflammatory response, this was not observed with smooth, spherical particles of comparable size or with larger particles. These findings indicate that hydroxyapatite particle characteristics dictate immune cell recruitment and the ensuing inflammatory response, providing an opportunity to tailor HA particle characteristics to regulate immune responses induced after biomaterial implantation.


Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial).
Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome. This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditioning is applied at the arm by 3 cycles of 5 minutes of ischemia and reperfusion. Primary endpoint is the incidence AF in the first 72 hours after surgery, detected using a Holter-monitor. Secondary endpoints include length-of-stay on the intensive care unit and in-hospital, and the occurrence of major adverse cardiovascular events at 30 days, 3 months and 1 year.Based on an expected incidence in the control group of 27%, 195 patients per group are needed to detect with 80% power a reduction by 45% following either pre- or postconditioning, while allowing for a 10% dropout and at an alpha of 0.05. With the combined intervention expected to be stronger, we need 75 patients in this group to detect a reduction in incidence of AF of 60%. The RICO-trial (the effect of Remote Ischemic Conditioning on atrial fibrillation and Outcome) is a randomized controlled multicenter trial, designed to investigate whether remote ischemic pre- and/or post-conditioning of the arm reduce the incidence of AF following CABG surgery. ClinicalTrials.gov under NCT01107184.


Model for infrared emission of water vapor/aerosol mixtures.
An equation modeling ir aerosol emission is presented with experimental data and spectra of low temperature steam from laboratory radiometric measurements. The equation, for the 8-13-micro ir continuum, predicts emissions for traces of liquid water aerosol comparable to those from Elsasser's equation attributed to water vapor. Several curves compare water absorptivity coefficients in the liquid and vapor phases and as applied to atmospheric measurements at the 10.6-micro CO(2) laser wavelength. Results indicate that water aerosols can account for major changes in radiance, even through apparently clear atmospheres. Ice crystals, by implication, represent another fertile field for study as absorbers and emitters.


The clinical management of HCV in the HIV-infected patient.
Chronic hepatitis C affects an estimated 170 million persons worldwide and due to shared transmission routes many persons are coinfected with HIV. Since the advent of HAART, HIV patients have longer life expectancy and suffer fewer AIDS-related complications. The result has been an increase in morbidity and mortality from HIV-associated non-AIDS conditions, with high rates of liver-related deaths resulting from HCV in the coinfected population. Coinfection with HIV is an independent predictor of liver disease progression, and proper staging of fibrosis is of critical importance in the coinfected patient. In contrast to HIV, it is possible to eradicate HCV infection; and undetectable viral load 12 weeks after cessation of therapy, or sustained viral response (SVR), is considered a clinical cure. As achievement of SVR has been associated with significantly reduced mortality from liver disease and liver disease complications, it is imperative that patients coinfected with HIV-HCV receive therapy for their HCV infection. The length of therapy with previously available interferon-based regimens added a significant burden to HIV-HCV-coinfected patients. Newer, all-oral, interferon-free regimens promise to simplify treatment regimens, reduce side-effect profiles, and demonstrate reduced drug interactions with numerous HAART regimens.


Purified human anti-Tn and anti-T antibodies specifically recognize carcinoma tissues.
Described in several epithelial cancer cells, Tn- (GalNAcα1-O-Ser/Thr) and T- (Galβ3GalNAcα1-O-Ser/Thr) antigens are examples of tumor-associated antigens. Increased expression of Tn- and T-antigens is associated with tumor invasion and metastasis, and patients with high concentration of anti-Tn and anti-T antibodies have a more benign evolution of pathology. Asialofetuin (ASF) and ovine submaxillary mucin (OSM) are two glycoproteins that expose T- and Tn-antigen, respectively. In this work, using ASF or OSM we affinity-purified anti-T and anti-Tn antibodies from normal human plasma and tested their ability to specifically recognize tumor human tissues. Whereas purified anti-T antibodies (purity degree increase of 127-fold, and 22% recovery) were mainly IgG, for purified anti-Tn antibodies (purity degree enhancement of 125-fold, and 26% yield) the IgM fraction was predominant over the IgG one. IgG2 subclass was significantly enriched in both purified antibody samples. Purified antibodies did not bind normal human tissue (0/42), although recognized malignant tissues from different origin such as colon carcinoma (11/77 by anti-Tn; 7/79 by anti-T), breast carcinoma (10/23 by anti-Tn; 7/23 by anti-T), and kidney carcinoma (45/51 by anti-Tn; 42/51 by anti-T). Our results suggest that purified human anti-Tn and anti-T antibodies have a potential as anti-tumor therapeutic agents; restoring their levels in human sera could positively affect the evolution of patients with epithelial tumor pathologies.


Polonium and lung cancer.
The alpha-radioactive polonium 210 (Po-210) is one of the most powerful carcinogenic agents of tobacco smoke and is responsible for the histotype shift of lung cancer from squamous cell type to adenocarcinoma. According to several studies, the principal source of Po-210 is the fertilizers used in tobacco plants, which are rich in polyphosphates containing radio (Ra-226) and its decay products, lead 210 (Pb-210) and Po-210. Tobacco leaves accumulate Pb-210 and Po-210 through their trichomes, and Pb-210 decays into Po-210 over time. With the combustion of the cigarette smoke becomes radioactive and Pb-210 and Po-210 reach the bronchopulmonary apparatus, especially in bifurcations of segmental bronchi. In this place, combined with other agents, it will manifest its carcinogenic activity, especially in patients with compromised mucous-ciliary clearance. Various studies have confirmed that the radiological risk from Po-210 in a smoker of 20 cigarettes per day for a year is equivalent to the one deriving from 300 chest X-rays, with an autonomous oncogenic capability of 4 lung cancers per 10000 smokers. Po-210 can also be found in passive smoke, since part of Po-210 spreads in the surrounding environment during tobacco combustion. Tobacco manufacturers have been aware of the alpha-radioactivity presence in tobacco smoke since the sixties.


Impact of community organization of women on perinatal outcomes in rural Bolivia.
An intervention to improve maternal and child health was conducted in a remote Bolivian province with limited access to modern medical facilities. The intervention focused on initiating and strengthening women's organizations, developing women's skills in problem identification and prioritization, and training community members in safe birthing techniques. Its impact was evaluated by comparing perinatal mortality rates and obstetric behavior among 409 women before and after the intervention. Perinatal mortality decreased from 117 deaths per 1,000 births before the intervention to 43.8 deaths per 1,000 births after. There was a significant increase in the number of women participating in women's organizations following the intervention, as well as in the number of organizations. The proportion of women receiving prenatal care and initiating breast-feeding on the first day after birth was also significantly larger. The number of infants attended to immediately after delivery likewise increased, but the change was not statistically significant. This study demonstrates that community organization can improve maternal and child health in remote areas.


Lactobacillus rhamnosus PB01 (DSM 14870) supplementation affects markers of sperm kinematic parameters in a diet-induced obesity mice model.
Probiotics have been proposed as alternatives to pharmacological products in several medical conditions including the modulation of obesity, which is frequently associated with poor semen quality. However, effects of probiotics on male fertility have been less investigated. This study assessed the effect of Lactobacillus rhamnosus PB01 (DSM-14870) on sperm kinematic parameters in Normal-weight (NW) and diet-induced obese (DIO) models. NW and DIO C57BL/6NTac mice were divided into two subgroups with or without a single daily dose (1x109CFU) of L. rhamnosus for four weeks. Sperm motility and kinematics together with blood lipid profiles and reproductive hormone levels were assessed using the sperm class analyzer system. Probiotic supplementation increased serum testosterone, LH and FSH levels in both NW and DIO groups resulting in significantly (P<0.05) higher velocity (VSL, VCL and VAP) and percentages of progressively motile sperm and significantly lower percentages of immotile sperm. Other kinematic parameters (Lin, STR, ALH and BCF) were also increased in both probiotic supplemented DIO and NW groups at the 10% level of significance. Probiotic supplemented DIO mice demonstrated significantly higher percentages of progressively motile sperm versus DIO controls. This study demonstrated the potential of L. rhamnosus PB01 as a regulatory agent with positive effects on weight loss and reproductive-hormones, significantly improving sperm motility and kinematic parameters in male DIO models.


Symmetrical peripheral gangrene: a rare complication of dengue fever.
Symmetric peripheral gangrene is associated with a variety of infective and non-infective etiologies. SPG is always presented with disseminated intravascular coagulation (DIC) and carries a higher mortality. Herein, we describe a 42-year-old female with dengue fever and rash developed bilateral symmetric dry gangrene of 2 nd and 3 rd toes. There was no history of taking B-blockers, ergot etc. All the peripheral pulses of the affected limbs were palpable. Color Doppler of lower limb vessels was done, which indicated normal flow. Blood was positive for Fibrin degradation products and D dimers. Patient was managed with IV fluids, LMWH, FFP etc. Her general condition improved within 72 hours with no further progression of gangrene.


Unbiased parallel detection of viral pathogens in clinical samples by use of a metagenomic approach.
Viral infectious diseases represent a major threat to public health and are among the greatest disease burdens worldwide. Rapid and accurate identification of viral agents is crucial for both outbreak control and estimating regional disease burdens. Recently developed metagenomic methods have proven to be powerful tools for simultaneous pathogen detection. Here, we performed a systematic study of the capability of the short-read-based metagenomic approach in the molecular detection of viral pathogens in nasopharyngeal aspirate samples from patients with acute lower respiratory tract infections (n = 16). Using the high-throughput capacity of ultradeep sequencing and a dedicated data interpretation method, we successfully identified seven species of known respiratory viral agents from 15 samples, a result that was consistent with results of conventional PCR assays. We also detected a coinfected case that was missed by regular PCR testing. Using the metagenomic data, 11 draft genomes of the abundantly detected viruses in the samples were reconstructed with 21.84% to 98.53% coverage. Our results show the power of the short-read-based metagenomic approach for accurate and parallel screening of viral pathogens. Although there are some inherent difficulties in applying this approach to clinical samples, including a lack of controls, limited specimen quantity, and high contamination rate, our work will facilitate further application of this unprecedented high-throughput method to clinical samples.


Comparison of upper and lower airway responses of two sensitized rat strains to inhaled antigen.
The purpose of the study was to investigate the relationships between upper airways responses and pulmonary responses of two strains of highly inbred rats to inhaled antigen. To do this we measured the upper and lower airways resistance for 60 min after challenge of Brown-Norway rats (BN; n = 13) and an inbred rat strain (MF; n = 11), derived from Sprague-Dawley, with aerosolized ovalbumin (OA). Rats were actively sensitized with OA (1 mg sc) using Bordetella pertussis as an adjuvant. Two weeks later the animals were anesthetized and challenged. Tracheal pressure, esophageal pressure, and airflow were measured, from which total pulmonary resistance was partitioned into upper airway and lower pulmonary resistance (RL). The peak upper airway response to inhaled OA was similar in BN (1.89 +/- 0.66 cmH2O.ml-1.s; n = 7) and MF (2.85 +/- 0.68 cmH2O.ml-1.s; n = 6). The lower airway response to OA challenge was substantially greater in BN, and RL changed from 0.07 +/- 0.01 to 0.34 +/- 0.13 (n = 6; P < 0.05). The MF did not have any significant increase in RL after challenge; the baseline RL was 0.12 +/- 0.02 and only reached a peak value of 0.15 +/- 0.05 (n = 5; P = NS). Lower airway responsiveness of BN (n = 10) to serotonin, an important mediator early allergic airway responses, was similar to MF (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)


Absolute numbers of lives saved and overdiagnosis in breast cancer screening, from a randomized trial and from the Breast Screening Programme in England.
To estimate the absolute numbers of breast cancer deaths prevented and the absolute numbers of tumours overdiagnosed in mammographic screening for breast cancer at ages 50-69 years. The Swedish Two-County randomized trial of mammographic screening for breast cancer, and the UK Breast Screening Programme in England, ages 50-69 years. We estimated the absolute numbers of deaths avoided and additional cases diagnosed in the study group (active study population) of the Swedish Two-County Trial, by comparison with the control group (passive study population). We estimated the same quantities for the mortality and incidence rates in England (1974-2004 and 1974-2003, respectively). We used Poisson regression for statistical inference. A substantial and significant reduction in breast cancer mortality was associated with screening in both the Two-County Trial (P < 0.001) and the screening programme in England (P < 0.001). The absolute benefits were estimated as 8.8 and 5.7 breast cancer deaths prevented per 1000 women screened for 20 years starting at age 50 from the Two-County Trial and screening programme in England, respectively. The corresponding estimated numbers of cases overdiagnosed per 1000 women screened for 20 years were, respectively, 4.3 and 2.3 per 1000. The benefit of mammographic screening in terms of lives saved is greater in absolute terms than the harm in terms of overdiagnosis. Between 2 and 2.5 lives are saved for every overdiagnosed case.


Impaired Visuospatial Short-Term Memory in Children with ADHD.
Previous studies provide clear evidence that visuospatial memory performance in children with attention-deficit/hyperactivity disorder (ADHD) is significantly lower than in typically developing children. In the present study, we investigated a major cause of their low performance using a spatial span test. Possibly, inattention resulting from lack of motivation or interest causes their low performance so that they do not correctly encode targets to be remembered. On the other hand, a deficit in temporary maintenance per se may cause their low performance; that is, their inefficient use of rehearsal during a retention interval may lead to memory traces' fast decay. Results in this study indicated that children with ADHD could sustain attention during the encoding phase. Furthermore, their performance at delayed recall was significantly lower than immediate recall, but delayed recall did not affect typically developing children's performance. These results provide evidence for the likelihood that a factor causing children with ADHD difficulty in temporarily maintaining visuospatial information is fast decay of memory traces as a result of inefficient use of rehearsal, not inattention in the encoding phase.


Verticalization of bacterial biofilms.
Biofilms are communities of bacteria adhered to surfaces. Recently, biofilms of rod-shaped bacteria were observed at single-cell resolution and shown to develop from a disordered, two-dimensional layer of founder cells into a three-dimensional structure with a vertically-aligned core. Here, we elucidate the physical mechanism underpinning this transition using a combination of agent-based and continuum modeling. We find that verticalization proceeds through a series of localized mechanical instabilities on the cellular scale. For short cells, these instabilities are primarily triggered by cell division, whereas long cells are more likely to be peeled off the surface by nearby vertical cells, creating an "inverse domino effect". The interplay between cell growth and cell verticalization gives rise to an exotic mechanical state in which the effective surface pressure becomes constant throughout the growing core of the biofilm surface layer. This dynamical isobaricity determines the expansion speed of a biofilm cluster and thereby governs how cells access the third dimension. In particular, theory predicts that a longer average cell length yields more rapidly expanding, flatter biofilms. We experimentally show that such changes in biofilm development occur by exploiting chemicals that modulate cell length.


Catalytic, Enantioselective syn-Diamination of Alkenes.
The enantioselective, vicinal diamination of alkenes represents one of the stereocontrolled additions that remains an outstanding challenge in organic synthesis. A general solution to this problem would enable the efficient and selective preparation of widely useful, enantioenriched diamines for applications in medicinal chemistry and catalysis. In this article, we describe the first enantioselective, syn-diamination of simple alkenes mediated by a chiral, enantioenriched organoselenium catalyst together with a N,N'-bistosyl urea as the bifunctional nucleophile and N-fluorocollidinium tetrafluoroborate as the stoichiometric oxidant. Diaryl, aryl-alkyl, and alkyl-alkyl olefins bearing a variety of substituents are all diaminated in consistently high enantioselectivities but variable yields. The reaction likely proceeds through a Se(II)/Se(IV) redox catalytic cycle reminiscent of the syn-dichlorination reported previously. Furthermore, the syn-stereospecificity of the transformation shows promise for highly enantioselective diaminations of alkenes with no strong steric or electronic bias.


Metoptic Canal and Warwick's Foramen: Incidence and Morphometric Analysis by Several Reference Points in the Human Orbit.
Several canals and foramens in the human orbit are well known in the literature. However, little is known about some minor canals or structures including metoptic canal and Warwick's foramen. The aim of the present study was to make morphometric measurements and to determine the incidence of the metoptic canal and Warwick's foramen in the Turkish population. Ninety-two dried human skulls were examined. All skulls were obtained from the Turkish population and collection of the Anatomy Department of the Akdeniz University. The metoptic canal and Warwick's foramen were identified in the skulls. Incidence of these structures and diameters were determined. Morphometric measurements were made using various reference points in the orbit. Of the 92 dry human skulls, the metoptic canal was detected in 20 of them. This canal was detected unilaterally. The metoptic canal was observed in 11 (11.9%) dry skulls in the right side, whereas it was observed in 9 (9.7%) dry skulls in the left side. There were no statistically significant differences according to the side for any of the measurements recorded (p>0.05). The Warwick's foramen was observed in 12 (13.0%) skulls of all dry skulls. This foramen was also present unilaterally and was right sided in 7 (7.6%) skulls and left sided in 5 (5.4%) skulls. Determination of additional foramen in the orbit is contributed to the literature. The presence of the metoptic canal and Warwick's foramen and their relationship with other structures in the orbit may have clinical significance in surgical operations.


Radioimmunotherapy in non-Hodgkin lymphoma: opinions of U.S. medical oncologists and hematologists.
Radioimmunotherapy is approved by the Food and Drug Administration for CD20 antigen-positive follicular and transformed non-Hodgkin lymphoma. The goal of this study was to obtain the opinion of hematologists and medical oncologists about CD20-directed radioimmunotherapy in the United States. An e-mail-based survey with 8 questions was sent to 4,239 oncologists and hematologists throughout the United States. Two hundred sixteen (5.0%) oncologists and hematologists responded to our survey. One hundred fifty-seven (72.7%) said they had referred patients with non-Hodgkin lymphoma for radioimmunotherapy in the last 24 mo. Different types of practices had significantly different concerns regarding this treatment. Compared with referring physicians from academic centers, those from nonacademic centers reported significantly higher concerns about the lack of a site to which to refer patients for treatment (P < 0.01), the lack of interest by nuclear physicians in this type of treatment (P < 0.01), and a referral process that they felt was too complicated (P < 0.01). They were also more concerned about an economically adverse effect on their own practices if they referred patients for radioimmunotherapy (P < 0.01). Referring physicians who perceived consolidation as a possible indication for radioimmunotherapy had significantly fewer concerns about an adverse effect on their own practice (P < 0.01) and about nonradioactive alternatives (P < 0.01). Seventy-nine (36.6%) responders thought radioimmunotherapy would probably grow in importance, and 52 (24.1%) responders thought it would definitely grow in importance. However, the group with a positive outlook about the future of radioimmunotherapy predicted a higher growth of radioimmunotherapy if they could administer it in their own offices (P < 0.05). Radioimmunotherapy was generally viewed positively by referring physicians. However, in addition to scientific concerns, barriers to the use of radioimmunotherapy included difficulty in referral, perceptions of a high cost of the treatment, concerns about negative financial outcomes related to referral, and an opinion that the treatment would be used more if given by medical oncologists in their own offices. For the growth of radioimmunotherapy, it appears crucial not only to demonstrate the treatment's safety and efficacy but also to streamline the referral process, to enhance collaboration between specialists, and-it appears-to develop economic incentives for the referring physician.


Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency.
T lymphocytes cultured from a patient (T.D.) with adenosine deaminase (ADA) deficiency expressed ADA activity in the normal range, inconsistent with her severe immunodeficiency, metabolic abnormalities, and with the absence of ADA activity in her B lymphocytes and other nucleated hematopoietic cells. ADA from T.D. T cells had normal Km, heat stability, and sensitivity to ADA inhibitors. Examination of HLA phenotype and polymorphic DNA loci indicated that T.D. was neither chimeric nor a genetic mosaic. Amplified and subcloned ADA cDNA from ADA+ T.D. T cells was shown by allele-specific oligonucleotide hybridization to possess the same mutations (Arg101----Trp, Arg211----His) previously found in the ADA-T.D. B cell line GM 2606 (Akeson, A. L., D. A. Wiginton, M. R. Dusing, J. C. States, and J. J. Hutton. 1988. J. Biol. Chem. 263:16291-16296). Our findings suggest that one of these mutant alleles can be expressed selectively in IL-2-dependent T cells as stable, active enzyme. Cultured T cells from other patients with the Arg211----His mutation did not express significant ADA activity, while some B cell lines from a patient with an Arg101----Gln mutation have been found to express normal ADA activity. We speculate that Arg101 may be at a site that determines degradation of ADA by a protease that is under negative control by IL-2 in T cells, and is variably expressed in B cells. Il-2 might increase ADA expression in T cells of patients who possess mutations of Arg101.


In Vitro and In Vivo Functional Characterization of Essence of Chicken as An Ergogenic Aid.
Essence of chicken is a popular Asian nutritional supplement that is often taken to improve metabolism and general health. Although used as a traditional remedy for combating fatigue and general health, there has been few studies investigating the ergogenic properties of chicken essence and its associated mechanism. We conducted a study to investigate the anti-fatigue and anti-oxidant properties of essence of chicken (EC) after exercise. Six weeks old male Institute of Cancer Research (ICR) mice were divided to four groups (10 mice/group) and were provided different doses of Essence of Chicken (EC): (1) Vehicle (water), (2) EC-0.5X (558 mg/kg), (3) EC-1X (1117 mg/kg), and (4) EC-2X (2234 mg/kg). EC supplementation could improve endurance and grip strength (p < 0.0001) and it had significant effects on the fatigue-related biochemical markers: ammonia, blood urea nitrogen (BUN), and creatine kinase (CK) levels were significantly lowered, while glucose blood levels and lactate clearance were improved after exercise challenge. Muscle and liver glycogen levels, muscle and liver superoxide dismutase (SOD), hepatic catalase (CAT), and glutathione (GSH) levels were observed to increase with EC supplementation. Preliminary in vitro data suggests that EC may have a beneficial effect in muscle mass and strength. No abnormalities were observed from pathohistological examination. Our study suggests that the EC could significantly improve exercise performance and endurance capacity and that the anti-oxidant properties of EC may be an important contributing factor to its anti-fatigue effects.


Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumor-initiating cells.
Triple-negative breast cancer (TNBC) high rate of relapse is thought to be due to the presence of tumor-initiating cells (TICs), molecularly defined as being CD44high/CD24-/low. TICs are resilient to chemotherapy and radiation. However, no currently accepted molecular target exists against TNBC and, moreover, TICs. Therefore, we sought the identification of kinase targets that inhibit TNBC growth and eliminate TICs. A genome-wide human kinase small interfering RNA (siRNA) library (691 kinases) was screened against the TNBC cell line SUM149 for growth inhibition. Selected siRNAs were then tested on four different breast cancer cell lines to confirm the spectrum of activity. Their effect on the CD44high subpopulation and sorted CD44high/CD24-/low cells of SUM149 also was studied. Further studies were focused on polo-like kinase 1 (PLK1), including its expression in breast cancer cell lines, effect on the CD44high/CD24-/low TIC subpopulation, growth inhibition, mammosphere formation, and apoptosis, as well as the activity of the PLK1 inhibitor, BI 2536. Of the 85 kinases identified in the screen, 28 of them were further silenced by siRNAs on MDA-MB-231 (TNBC), BT474-M1 (ER+/HER2+, a metastatic variant), and HR5 (ER+/HER2+, a trastuzumab-resistant model) cells and showed a broad spectrum of growth inhibition. Importantly, 12 of 28 kinases also reduced the CD44high subpopulation compared with control in SUM149. Further tests of these 12 kinases directly on a sorted CD44high/CD24-/low TIC subpopulation of SUM149 cells confirmed their effect. Blocking PLK1 had the greatest growth inhibition on breast cancer cells and TICs by about 80% to 90% after 72 hours. PLK1 was universally expressed in breast cancer cell lines, representing all of the breast cancer subtypes, and was positively correlated to CD44. The PLK1 inhibitor BI 2536 showed similar effects on growth, mammosphere formation, and apoptosis as did PLK1 siRNAs. Finally, whereas paclitaxel, doxorubicin, and 5-fluorouracil enriched the CD44high/CD24-/low population compared with control in SUM149, subsequent treatment with BI 2536 killed the emergent population, suggesting that it could potentially be used to prevent relapse. Inhibiting PLK1 with siRNA or BI 2536 blocked growth of TNBCs including the CD44high/CD24-/low TIC subpopulation and mammosphere formation. Thus, PLK1 could be a potential therapeutic target for the treatment of TNBC as well as other subtypes of breast cancer.


On algebraic properties of the sub-block of zero field hyperfine Hamiltonian with penultimate total spin projection for arbitrary hyperfine structure, and field dependence of radical pair recombination probability in the vicinity of zero field.
Basic algebraic arguments demonstrate that the probability of radical pair recombination in low field for an arbitrary pair with Hamiltonian confined to Zeeman and isotropic hyperfine interactions contains two additive contributions linear with applied field with equal, but opposite in sign, proportionality factors. Their weights are determined by the probability of having all nuclear spins along the field in the initial electron-singlet state of the pair, and in the case of equilibrium with respect to nuclear spins, the two contributions completely compensate the field dependences of each other, producing an additive term in the singlet yield with zero derivative. However, if the nuclear set is polarized, a linear skew proportional to polarization appears, introducing anisotropy in the intrinsically spherically symmetric system. The key element in this derivation is guaranteed nondegeneracy of the eigenvalues of the "penultimate" (Mmax - 1) block of the Hamiltonian for a radical with any number of distinct spin-1/2 nuclei in zero field, which leads to guaranteed applicability of the first-order nondegenerate perturbation theory with nonvanishing linear in field admixture of states, persisting all the way into the final expression for singlet yield for a pair with an arbitrary isotropic hyperfine structure. We argue that this behavior of the field dependence of recombination yield is representative of a radical pair of an arbitrarily complex hyperfine structure; this may be a possible mechanism for anisotropic response ("chemical compass") for an isotropic radical pair based system with isotropic-only internal interactions and anisotropy introduced via the initial state of nuclei, while such an approach may complement the usually needed numerical simulations.


Abnormal functional lateralization and activity of language brain areas in typical specific language impairment (developmental dysphasia).
Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting structural language (n = 21), to a matched group of typically developing children using a panel of four language tasks neither requiring reading nor metalinguistic skills, including two auditory lexico-semantic tasks (category fluency and responsive naming) and two visual phonological tasks based on picture naming. Data processing involved normalizing the data with respect to a matched pairs paediatric template, groups and between-groups analysis, and laterality indices assessment within regions of interest using single and combined task analysis. Children with specific language impairment exhibited a significant lack of left lateralization in all core language regions (inferior frontal gyrus-opercularis, inferior frontal gyrus-triangularis, supramarginal gyrus and superior temporal gyrus), across single or combined task analysis, but no difference of lateralization for the rest of the brain. Between-group comparisons revealed a left hypoactivation of Wernicke's area at the posterior superior temporal/supramarginal junction during the responsive naming task, and a right hyperactivation encompassing the anterior insula with adjacent inferior frontal gyrus and the head of the caudate nucleus during the first phonological task. This study thus provides evidence that this subtype of specific language impairment is associated with atypical lateralization and functioning of core language areas.


Post-natal outcomes of antenatally diagnosed intra-abdominal cysts: a 22-year single-institution series.
The aim of this study was to establish the post-natal diagnosis and outcome of antenatally diagnosed intra-abdominal cysts between 1991 and 2013 at our institution. All antenatally diagnosed intra-abdominal cysts between 1991 and 2013 were identified using a foetal anomaly database. The cysts were monitored for resolution. In all cases where the cyst had not resolved antenatally, additional post-natal scans were conducted. Antenatal diagnosis, post-natal diagnosis and outcomes were also recorded. 118 cases of antenatal intra-abdominal cysts were identified over the 22-year study period with a 98 % live birth rate. The overall accuracy of an antenatal diagnosis at our institution was 92 %. 26 cases (22 %) resolved spontaneously in utero, the majority of which (77 %) were ovarian in nature. Four tumour cases were identified in the series, which included two neuroblastomas, one yolk sac tumour and one teratoma. 90 cysts persisted post-natally with 52 % requiring surgery. These primarily included choledochal and enteric duplication cysts as well as symptomatic solid organ cysts. Diagnostic revision was limited to 8 % of cases over the study period with an overall improvement over the last decade. Overall, 40 % of all antenatally diagnosed cysts required surgical intervention. In those cysts that persisted post-natally, 52 % required surgery. A fifth of prenatally diagnosed intra-abdominal cysts will resolve with most ovarian cysts regressing in utero. Half of all persistent cysts will, however, require surgical intervention. These data are useful for prenatal counselling and demonstrates the important role played by the paediatric surgeon in the overall management of intra-abdominal cysts.


Nonequilibrium Entropic Bounds for Darwinian Replicators.
Life evolved on our planet by means of a combination of Darwinian selection and innovations leading to higher levels of complexity. The emergence and selection of replicating entities is a central problem in prebiotic evolution. Theoretical models have shown how populations of different types of replicating entities exclude or coexist with other classes of replicators. Models are typically kinetic, based on standard replicator equations. On the other hand, the presence of thermodynamical constraints for these systems remain an open question. This is largely due to the lack of a general theory of statistical methods for systems far from equilibrium. Nonetheless, a first approach to this problem has been put forward in a series of novel developements falling under the rubric of the extended second law of thermodynamics. The work presented here is twofold: firstly, we review this theoretical framework and provide a brief description of the three fundamental replicator types in prebiotic evolution: parabolic, malthusian and hyperbolic. Secondly, we employ these previously mentioned techinques to explore how replicators are constrained by thermodynamics. Finally, we comment and discuss where further research should be focused on.


Detection of malignant mesothelioma using nuclear structure of mesothelial cells in effusion cytology specimens.
Mesothelioma is a form of cancer generally caused from previous exposure to asbestos. Although it was considered a rare neoplasm in the past, its incidence is increasing worldwide due to extensive use of asbestos. In the current practice of medicine, the gold standard for diagnosing mesothelioma is through a pleural biopsy with subsequent histologic examination of the tissue. The diagnostic tissue should demonstrate the invasion by the tumor and is obtained through thoracoscopy or open thoracotomy, both being highly invasive surgical operations. On the other hand, thoracocentesis, which is removal of effusion fluid from the pleural space, is a far less invasive procedure that can provide material for cytological examination. In this study, we aim at detecting and classifying malignant mesothelioma based on the nuclear chromatin distribution from digital images of mesothelial cells in effusion cytology specimens. Accordingly, a computerized method is developed to determine whether a set of nuclei belonging to a patient is benign or malignant. The quantification of chromatin distribution is performed by using the optimal transport-based linear embedding for segmented nuclei in combination with the modified Fisher discriminant analysis. Classification is then performed through a k-nearest neighborhood approach and a basic voting strategy. Our experiments on 34 different human cases result in 100% accurate predictions computed with blind cross validation. Experimental comparisons also show that the new method can significantly outperform standard numerical feature-type methods in terms of agreement with the clinical diagnosis gold standard. According to our results, we conclude that nuclear structure of mesothelial cells alone may contain enough information to separate malignant mesothelioma from benign mesothelial proliferations.


Effects of tap water, electrolyte solution, and spontaneous and furosemide-stimulated urinary excretion on thirst.
To contrast the effects of various modifications of body fluid volumes on thirst as reported by healthy volunteers. Ten male volunteers aged between 19 and 37 years (mean 22 years) underwent four experiments each, which comprised infusion of 400-800 mL of acetated Ringer's solution and intake of 600 mL of tap water. Half of the experiments were preceded by volume depletion (median 1.7 L) with furosemide. A visual analogue scale (0-100 mm) was used to assess perceived thirst during each experiment. Volume depletion (P < 0.001) and tap water (P < 0.03) both affected thirst by 13 mm per L of fluid, whereas spontaneous diuresis and infusion of Ringer's acetate did not significantly change the thirst rating (multiple regressions). More detailed analyses showed that the volume depletion increased the median (25th-75th percentiles) thirst rating from 28 mm (21-43) to 59 mm (46-72, P < 0.001) while no change occurred in those who were only slightly thirsty (< 30 mm) before the volume depletion began. Ringer's solution alleviated thirst in those who were very thirsty, but tended to increase thirst in the volunteers who were not thirsty before the infusion. Similarly, hydration with tap water decreased thirst (by 24 mm, P < 0.04) in those who were thirsty (> 60 mm) while the others reported no change. The change in thirst rating during volume depletion, administration of Ringer's acetate, and ingestion of tap water were all dependent on the thirst rating obtained when the manipulation of the body fluid volume was initiated.


The influence of nonmarital childbearing on the formation of first marriages.
We document a negative association between nonmarital childbearing and the subsequent likelihood of first marriage in the United States, controlling for a variety of potentially confounding influences. Nonmarital childbearing does not appear to be driven by low expectations of future marriage. Rather, it tends to be an unexpected and unwanted event, whose effects on a woman's subsequent likelihood of first marriage are negative on balance. We find that women who bear a child outside marriage and who receive welfare have a particularly low probability of marrying subsequently, although there is no evidence that AFDC recipients have lower expectations of marriage. In addition, we find no evidence that stigma associated with nonmarital childbearing plays an important role in this process or that the demands of children significantly reduce unmarried mothers' time for marriage market activities.


The CLEF corpus: semantic annotation of clinical text.
The Clinical E-Science Framework (CLEF) project is building a framework for the capture, integration and presentation of clinical information: for clinical research, evidence-based health care and genotype-meets-phenotype informatics. A significant portion of the information required by such a framework originates as text, even in EHR-savvy organizations. CLEF uses Information Extraction (IE) to make this unstructured information available. An important part of IE is the identification of semantic entities and relationships. Typical approaches require human annotated documents to provide both evaluation standards and material for system development. CLEF has a corpus of clinical narratives, histopathology reports and imaging reports from 20 thousand patients. We describe the selection of a subset of this corpus for manual annotation of clinical entities and relationships. We describe an annotation methodology and report encouraging initial results of inter-annotator agreement. Comparisons are made between different text sub-genres, and between annotators with different skills.


Return to Play and Decreased Performance After Anterior Cruciate Ligament Reconstruction in National Football League Defensive Players.
Anterior cruciate ligament (ACL) injuries occur commonly in football. Recent work has reported ACL reconstruction (ACLR) as one of several orthopaedic procedures with unfavorable outcomes for professional athletes. The performance impact to defensive players after surgery has not been quantified. To quantify the effect of ACLR on the performance of defensive players by comparing them to a cohort of matched controls as well as to measure the effect of ACLR on athletes' career length in the National Football League (NFL). Case-control and cohort study; Level of evidence, 3. Thirty-eight NFL defensive players with a history of ACLR from 2006 to 2012 were identified. For each injured player, a matched control player was identified. Demographic and performance statistics were collected from the online NFL player database. Players who returned after ACLR (n = 23) were compared with players who did not return (n = 15) using t tests and chi-squared analyses. Similarly, players who returned after ACLR (n = 23) were compared with their matched controls with t tests and chi-squared analyses. Two-way repeated-measures analysis of variance was utilized to test for significant differences between performance before and after the season of the injury for the players in the ACLR group who returned (n = 23) and for their matched controls. Kaplan-Meier analysis was performed to test for differences in the rate of retirement between the groups. For all analyses, P values <.05 were considered significant. Approximately 74% (28/38) of athletes who underwent ACLR returned to play at least 1 NFL game, and 61% (23/38) successfully returned to play at least half a season (ie, 8 games). Athletes in the ACLR group who returned retired from the NFL significantly sooner and more often after surgery than their matched controls. In the seasons leading up to their injury, athletes who successfully returned to play started a greater percentage of their games (81%) and made more solo tackles per game (3.44 ± 1.47) compared with athletes in the ACLR group who did not return to play (54% and 1.82 ± 1.17, respectively) and compared with healthy control players (52% and 1.77 ± 1.19, respectively). After the season of surgery, athletes in the ACLR group who returned to play decreased to 57% games started and 2.38 ± 1.24 solo tackles per game, while their matched controls suffered no significant decreases. Players who successfully returned were above-average NFL players before their injury but comparatively average after their return.


Genotoxicity of Copper and Nickel Nanoparticles in Somatic Cells of Drosophila melanogaster.
Copper and nickel nanoparticles (Cu-NPs and Ni-NPs, respectively) are used in a variety of industrial applications, such as semiconductors, catalysts, sensors, and antimicrobial agents. Although studies on its potential genotoxicity already exist, few of them report in vivo data. In the present study we have used the wing-spot assay in Drosophila melanogaster to determine the genotoxic activity of Cu-NPs and Ni-NPs, and these data have been compared with those obtained with their microparticle forms (MPs). Additionally, a complete physical characterization of NPs using transmission electronic microscopy (TEM), dynamic light scattering (DLS), and laser Doppler velocimetry (LDV) techniques was also performed. Results obtained with Cu-NPs and Cu-MPs indicate that both failed to induce an increase in the frequency of mutant spots formation in the wings of the adults, suggesting a lack of genotoxicity in somatic cells of D. melanogaster. However, when Ni-NPs and Ni-MPs were evaluated, a significant increase of small single spots and total mutant spots was observed only for Ni-NPs (P<0.05) at the highest dose assessed. Thus, the genotoxicity of Ni-NPs seem to be related to their nanoscale size, because no genotoxic effects have been reported with their microparticles and ions. This study is the first assessing the in vivo genotoxic potential of Cu-NPs and Ni-NPs in the Drosophila model.


Caesarean section and hospitalization for respiratory syncytial virus infection: a population-based study.
Hospitalization for respiratory syncytial virus (RSV) infection and asthma share common determinants, and meta-analyses indicate that children delivered by caesarean section (CS) are at increased risk of asthma. We aimed to investigate whether birth by CS is associated with an increased risk of hospitalization for RSV illness. This was a population-based national register-based cohort study, conducted between January, 1997 and June, 2003, which included all children born in Denmark and all hospitalizations for RSV disease in them from 0 to 23 months of age. We used Cox regression with adjustment for prematurity, asphyxia, birthweight, multiple births, single parenthood, maternal smoking during pregnancy, older siblings and asthma diagnoses up to 2 weeks before hospitalization for RSV infection, to compare the effects of acute or elective CS versus vaginal delivery, on subsequent hospitalization for RSV disease. A test for homogeneity was used to assess for effect over time. 399,175 children with 10,758 hospitalizations for RSV illness were included; 31,715 were born by acute CS and 30,965 by elective CS. Adjusted hazard ratios for hospitalization for RSV infection in children born by acute CS and by elective CS were 1.09 (1.01-1.17) and 1.27 (1.19-1.36), respectively. The effect of elective CS remained unchanged throughout the first 2 years of life (P = 0.53), whereas the effect of acute CS was only present in the second year of life (P = 0.001). Delivery by caesarian section is associated with an increased risk of hospitalization for RSV infection. This effect continues at least throughout the first 2 years of life.


Multiple wavelength illumination in flow cytometry using a single arc lamp and a dispersing element.
The principle of a multiple wavelength illumination method for flow cytometers, based upon a combination of a helium-neon laser and an arc lamp as illumination sources is described. By using a prism, the light from the arc lamp is dispersed and the different colors are imaged at different places on the sample stream. The small angle light scattering from the helium-neon laser light is measured as a relevant parameter and serves as a trigger signal for subsequent measurements of fluorescence or scattering of light from the arc lamp. Two experimental systems are described utilizing this principle: a system where the emission is detected orthogonally with respect to the direction of the illumination beams, and an epi-illumination system. With the orthogonal set-up multiple wave-length right angle scattering measurements are possible. This is illustrated by showing that the orthogonal scattering from erythrocytes is strongly dependent on the illumination wavelength. It is further shown that the apparatus is suitable for the measurement of intracellular pH using the pH dependence of the excitation spectrum of fluorescein. The epi-illumination system allows excitation of two (or more) fluorescent dyes with different excitation spectra. In this case the emission spectra of the fluorescent dyes may overlap substantially. This is shown by simultaneous measurement of DNA and protein of Chinese hamster lung cells using mitramycin and tetramethyl rhodamin isothiocyanate (TRITC).


Differentially expressed immune-related genes in hemocytes of the pearl oyster Pinctada fucata against allograft identified by transcriptome analysis.
The pearl oyster Pinctada fucata is commonly cultured for marine pearls in China. To culture pearls, a mantle piece from a donor pearl oyster is grafted with a nucleus into a receptor. This transplanted mantle piece may be rejected by the immune system of the recipient oyster, thus reducing the success of transplantation. However, there have been limited studies about the oyster's immune defense against allograft. In this study, hemocyte transcriptome analysis was performed to detect the immune responses to allograft in P. fucata at 0 h and 48 h after a transplant. The sequencing reaction produced 92.5 million reads that were mapped against the reference genome sequences of P. fucata. The Gene Ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to identify all immune-related differentially expressed genes (DEGs). Compared with patterns at 0 h, a total of 798 DEGs were identified, including 410 up-regulated and 388 down-regulated genes at 48 h. The expression levels of interleukin receptor and toll-like receptor in hemocytes were increased significantly 48 h post-transplant, indicating that the oyster immune response was induced. Finally, altered levels of 18 randomly selected immune-related DEGs were confirmed by quantitative real-time PCR (qRT-PCR). Our results provide the basis for further analysis of the immune rejection of allotransplantation.


DNA stem-loop structures in oligopurine-oligopyrimidine triplexes.
Closed circular DNA containing polypurine-polypyrimidine sequences can adopt a triple helical stem-loop structure under supercoiling pressure. We describe an automated procedure for building model loops and its application to the investigation of the polypyrimidine loop at the end of such a triple helical stem. All possible combinations of 3'-stacked and 5'-stacked structures have been examined for loops containing three, four, five, and six nucleotides. The lowest energy conformation is a four-membered loop with all bases stacked on the strand at the 3' end of the loop. The model predicts that sequences (GA)n, (GGGA)n and (GAAA)n should form the stem-loop structure more easily than (GGA)n and (GAA)n. It is also predicted that when a polypurine-polypyrimidine sequence converts from a double stranded structure to a triple stranded stem-loop, the most favorable conditions are those where an even number of basepairs makes the transition. Experimental tests of these predictions are also described.


Entering the Double Digits-Ewing Sarcoma In Adult Maxilla.
Ewing sarcoma is a rare malignant pediatric sarcoma of bone and soft tissues, which is more unusual in head and neck region. Although the exact histogenesis is still unknown, various cells have been proposed as cells of origin namely, endothelial, hematopoietic, fibroblastic, mesenchymal stem cells or neural derived mesenchymal stem cells. ES is more common in younger age group and among the gnathic bones, mandible is affected more than maxilla. This paper presents the first case of Ewing Sarcoma in the maxilla being reported in the adult age group from India and among the very few reported worldwide.


Promoting Nursing Students' Clinical Learning Through a Mobile e-Portfolio.
Portfolios have been advocated in nursing education to help student link theory and practice. In this study, we document the development of a mobile e-portfolio-based system, which was used to improve nursing education. The e-portfolio-based system has the advantage of allowing students to record, assess, and reflect upon their learning whether at school, a clinical site, or at home. This e-portfolio system was field tested in a 3-week psychiatric nursing practicum session involving 10 female students who were enrolled in a junior nursing college. A mixed-methods study combining qualitative and quantitative data was conducted to investigate the effects of using the system. The results of the study demonstrated that students made professional progress in both theory and practice after using the e-portfolio system. The system could also promote self-regulated learning in clinical context. Students displayed very positive attitudes overall when using the system, although there were some occasional stresses and technical difficulties. Important factors when implementing such a system included the following: adopting the proper mobile device, providing students with clear guidance on constructing the e-portfolio, and how to use the e-portfolio in a clinical setting.


Spin-polarized conceptual density functional theory study of the regioselectivity in ring closures of radicals.
The regioselectivity of ring-forming radical reactions is investigated within the framework of the so-called spin-polarized conceptual density functional theory. Two different types of cyclizations were studied. First, a series of model reactions of alkyl- and acyl-substituted radicals were investigated. Next, attention was focused on the radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals (a three-step mechanism). In both of these reactions, the approaching radical (carbon or nitrogen centered) adds to a carbon-carbon double bond within the same molecule to form a radical ring compound. In this process, the number of electrons is changing from a local point of view (a charge transfer occurs from one part of the molecule to another one) at constant global spin number Ns (both the reactant and the product ring compound are in the doublet state). It is shown that the experimentally observed regioselectivities for these ring-closure steps can be predicted using the spin-polarized Fukui functions for radical attack, f0NN(r).


Arterial Hypertension in Children.
Pharmacological treatment of arterial hypertension in children is mainly based on individual experience, but there is evidence that blocking the angiotensin system reduces systolic and diastolic blood when compared to placebo, and these drugs are safe to use for a short duration, also in children under 6 years of age. Blocking the angiotensin system either by angiotensin-converting enzyme inhibitors or by antagonizing the angiotensin 1 receptor is effective, but did not display a consistent dose-response relationship with escalating doses, but the effective doses are known. Calcium channel antagonists are effective antihypertensives in children, but the evidence is limited. Based on small-sized studies, beta-blockers modestly reduce systolic blood pressure, but have no significant effect on diastolic blood pressure compared to placebo. They act in combination to antagonize reflex tachycardia induced by vasodilators. The most commonly used antihypertensive agents are safe to use in short-term studies.


Localization of discontinuous epitopes of herpes simplex virus glycoprotein D: use of a nondenaturing ("native" gel) system of polyacrylamide gel electrophoresis coupled with Western blotting.
Previously, a panel of monoclonal antibodies (MCAb) was used to define specific epitopes of herpes simplex virus glycoprotein D (gD) (R. J. Eisenberg et al., J. Virol. 53:634-644, 1985). Three groups of antibodies recognized continuous epitopes; group VII reacted with residues 11 to 19 of the mature protein (residues 36 to 44 of the predicted sequence), group II reacted with residues 272 to 279, and group V reacted with residues 340 to 356. Four additional antibody groups recognized discontinuous epitopes of gD, since their reactivity was lost when the glycoprotein was denatured by reduction and alkylation. Our goal in this study was to localize more precisely the discontinuous epitopes of gD. Using a nondenaturing system of polyacrylamide gel electrophoresis ("native" gel electrophoresis) coupled to Western blotting, we analyzed the antigenic activity of truncated forms of gD. These fragments were generated either by recombinant DNA methods or by cleavage of purified native gD-1 (gD obtained from herpes simplex virus type 1) and gD-2 (gD obtained from herpes simplex virus type 2) with Staphylococcus aureus protease V8. Antibodies in groups III, IV, and VI recognized three truncated forms of gD-1 produced by recombinant DNA methods, residues 1 to 287, 1 to 275, and 1 to 233. Antibodies in group I recognized the two larger forms but did not react with the gD-1 fragment of residues 1 to 233. On the basis of these and previous results, we concluded that a protion of epitope I was located within residues 233 to 259 and that epitopes III, IV, and VI were upstream of residue 233. Antibodies to continuous epitopes identified protease V8 fragments of gD-1 and gD-2 that contained portions of either the amino or carboxy regions of the proteins. None of the V8 fragments, including a 34K polypeptide containing residues 227 to 369, reacted with group I antibodies. This result indicated that a second portion of epitope I was located upstream of residue 227. Two amino-terminal fragments of gD-1, 33K and 30K, reacted with group III, IV, and VI antibodies. A 33K fragment of gD-2 reacted with group III antibodies. Based on their size and reactivity with endo-beta-N-acetylglycosaminidase F, we hypothesized that the 33K and 30K molecules represented residues 1 to 226 and 1 to 182 of gD-1, respectively. These results suggest that epitopes III, IV, and VI are located within the first 182 residues of gD.(ABSTRACT TRUNCATED AT 400 WORDS)


Lung Ultrasound Findings in Patients With Coronavirus Disease (COVID-19).
OBJECTIVE. Although chest CT is the standard imaging modality in early diagnosis and management of coronavirus disease (COVID-19), the use of lung ultrasound (US) presents some advantages over the use of chest CT and may play a complementary role in the workup of COVID-19. The objective of our study was to investigate US findings in patients with COVID-19 and the relationship of the US findings with the duration of symptoms and disease severity. MATERIALS AND METHODS. From March 3, 2020, to March 30, 2020, consecutive patients with a positive reverse transcriptase polymerase chain reaction test result for the virus that causes COVID-19 were enrolled in this study. Lung US was performed, and the imaging features were analyzed. The Fisher exact test was used to compare the percentages of patients with each US finding between groups with different symptom durations and disease severity. RESULTS. Our study population comprised 28 patients (14 men and 14 women; mean age ± SD, 59.8 ± 18.3 years; age range, 21-92 years). All 28 patients (100.0%, 28/28) had positive lung US findings. The most common findings were the following: B-lines (100.0%, 28/28), consolidation (67.9%, 19/28), and a thickened pleural line (60.7%, 17/28). A thickened pleural line was observed in a higher percentage of patients with a longer duration of the disease than in those with a shorter duration of the disease, and pulmonary consolidations were more common in severe and critical cases than in moderate cases. CONCLUSION. Typical lung US findings in patients with COVID-19 included B-lines, pulmonary consolidation, and a thickened pleural line. In addition, our results indicate that lung US findings can be be used to reflect both the infection duration and disease severity.


Islands within islands: two montane palaeo-endemic birds impacted by recent anthropogenic fragmentation.
Anthropogenic habitat fragmentation of species that live in naturally patchy metapopulations such as mountaintops or sky islands experiences two levels of patchiness. Effects of such multilevel patchiness on species have rarely been examined. Metapopulation theory suggests that patchy habitats could have varied impacts on persistence, dependent on differential migration. It is not known whether montane endemic species, evolutionarily adapted to natural patchiness, are able to disperse between anthropogenic fragments at similar spatial scales as natural patches. We investigated historic and contemporary gene flow between natural and anthropogenic patches across the distribution range of a Western Ghats sky-island-endemic bird species complex. Data from 14 microsatellites for 218 individuals detected major genetic structuring by deep valleys, including one hitherto undescribed barrier. As expected, we found strong effects of historic genetic differentiation across natural patches, but not across anthropogenic fragments. Contrastingly, contemporary differentiation (D(PS)) was higher relative to historic differentiation (F(ST)) in anthropogenic fragments, despite the species' ability to historically traverse shallow valleys. Simulations of recent isolation resulted in high D(PS)/F(ST) values, confirming recent isolation in Western Ghats anthropogenic fragments and also suggesting that this ratio can be used to identifying recent fragmentation in the context of historic connectedness. We suggest that in this landscape, in addition to natural patchiness affecting population connectivity, anthropogenic fragmentation additionally impacts connectivity, making anthropogenic fragments akin to islands within natural islands of montane habitat, a pattern that may be recovered in other sky-island systems.


Evidence-based chlorination targets for household water safety in humanitarian settings: Recommendations from a multi-site study in refugee camps in South Sudan, Jordan, and Rwanda.
The current Sphere guideline for water chlorination in humanitarian emergencies fails to reliably ensure household water safety in refugee camps. We investigated post-distribution chlorine decay and household water safety in refugee camps in South Sudan, Jordan, and Rwanda between 2013-2015 with the goal of demonstrating an approach for generating site-specific and evidence-based chlorination targets that better ensure household water safety than the status quo Sphere guideline. In each of four field studies we conducted, we observed how water quality changed between distribution and point of consumption. We implemented a nonlinear optimization approach for the novel technical challenge of modelling post-distribution chlorine decay in order to generate estimates on what free residual chlorine (FRC) levels must be at water distribution points, in order to provide adequate FRC protection up to the point of consumption in households many hours later at each site. The site-specific FRC targets developed through this modelling approach improved the proportion of households having sufficient chlorine residual (i.e., ≥0.2 mg/L FRC) at the point of consumption in three out of four field studies (South Sudan 2013, Jordan 2014, and Rwanda 2015). These sites tended to be hotter (i.e., average mid-afternoon air temperatures >30°C) and/or had poorer water, sanitation, and hygiene (WASH) conditions, contributing to considerable chlorine decay between distribution and consumption. Our modelling approach did not work as well where chlorine decay was small in absolute terms (Jordan 2015). In such settings, which were cooler (20 to 30°C) and had better WASH conditions, we found that the upper range of the current Sphere chlorination guideline (i.e., 0.5 mg/L FRC) provided sufficient residual chlorine for ensuring household water safety up to 24 hours post-distribution. Site-specific and evidence-based chlorination targets generated from post-distribution chlorine decay modelling could help improve household water safety and public health outcomes in refugee camp settings where the current Sphere chlorination guideline does not provide adequate residual protection. Water quality monitoring in refugee/IDP camps should shift focus from distribution points to household points of consumption in order to monitor if the intended public health goal of safe water at the point of consumption is being achieved.


More or less CHAOS: case report and literature review suggesting the existence of a distinct subtype of congenital high airway obstruction syndrome.
Congenital obstruction of the upper airway (CHAOS) is a rare, usually lethal abnormality. A literature review of 36 prenatally diagnosed cases of CHAOS and the analysis of our own case suggest the existence of a distinct subtype of CHAOS, raising important implications for diagnosis and management. Serial fetal ultrasound examinations at 17-23 weeks' gestation showed hyperechoic and enlarged lungs, mediastinal shift, flattened diaphragm, polyhydramnios and apparently fluid-filled esophagus, findings interpreted as bilateral cystic adenomatoid malformation Type III. Ultrasound findings normalized around 32 weeks. The diagnosis of CHAOS was made after birth at term by direct laryngoscopy prompted by ventilatory difficulties and failed attempts at intubation. A pinhole opening posterior to the cricoid cartilage allowed the passage of an endotracheal tube. Based on observations in our case and those of five similar cases in the literature, we describe for the first time a subtype of CHAOS that is characterized by minor pharyngotracheal or laryngotracheal communications and associated with a less severe natural history and even resolution of ultrasound findings. In spite of this, a high index of awareness should be maintained because resolution of ultrasound findings does not necessarily indicate resolution of underlying pathology.


Transcriptional Profiling in Experimental Visceral Leishmaniasis Reveals a Broad Splenic Inflammatory Environment that Conditions Macrophages toward a Disease-Promoting Phenotype.
Visceral Leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani, is characterized by relentlessly increasing visceral parasite replication, cachexia, massive splenomegaly, pancytopenia and ultimately death. Progressive disease is considered to be due to impaired effector T cell function and/or failure of macrophages to be activated to kill the intracellular parasite. In previous studies, we used the Syrian hamster (Mesocricetus auratus) as a model because it mimics the progressive nature of active human VL. We demonstrated previously that mixed expression of macrophage-activating (IFN-γ) and regulatory (IL-4, IL-10, IL-21) cytokines, parasite-induced expression of macrophage arginase 1 (Arg1), and decreased production of nitric oxide are key immunopathologic factors. Here we examined global changes in gene expression to define the splenic environment and phenotype of splenic macrophages during progressive VL. We used RNA sequencing coupled with de novo transcriptome assembly, because the Syrian hamster does not have a fully sequenced and annotated reference genome. Differentially expressed transcripts identified a highly inflammatory spleen environment with abundant expression of type I and type II interferon response genes. However, high IFN-γ expression was ineffective in directing exclusive M1 macrophage polarization, suppressing M2-associated gene expression, and restraining parasite replication and disease. While many IFN-inducible transcripts were upregulated in the infected spleen, fewer were induced in splenic macrophages in VL. Paradoxically, IFN-γ enhanced parasite growth and induced the counter-regulatory molecules Arg1, Ido1 and Irg1 in splenic macrophages. This was mediated, at least in part, through IFN-γ-induced activation of STAT3 and expression of IL-10, which suggests that splenic macrophages in VL are conditioned to respond to macrophage activation signals with a counter-regulatory response that is ineffective and even disease-promoting. Accordingly, inhibition of STAT3 activation led to a reduced parasite load in infected macrophages. Thus, the STAT3 pathway offers a rational target for adjunctive host-directed therapy to interrupt the pathogenesis of VL.


Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist.
Irritable bowel syndrome (IBS) represents one of the most common gastrointestinal-related diagnoses. Although the precise etiologic basis of IBS is not known, a common presenting symptom is abdominal pain or discomfort that is thought to develop, at least in part, from a heightened awareness of visceral nociceptive input. Agents capable of reducing this heightened visceral nociception would, therefore, have utility in the treatment of IBS. In this study we evaluated the effects of intravenous and intracerebroventricular administration of a 5-HT3 receptor antagonist, alosetron, on blood pressure changes associated with rectal distension in anesthetized and awake dogs. This vasoactive reflex serves as a model for visceral nociception. For intracerebroventricular studies, the cerebroventricular guides were placed over the lateral ventricle. In anesthetized studies, blood pressure was measured by femoral artery cannulation. In awake studies, blood pressure was monitored by noninvasive measurement. A rectal balloon was placed in the rectum of each dog and maintained throughout the experiments. Each dose of alosetron was given to the dogs as an intravenous or intracerebroventricular bolus, and every 30 min the rectal balloon was inflated and blood pressure responses observed. In both anesthetized and awake dogs alosetron produced a significant inhibition of the vasoactive reflex. In particular, alosetron showed high potency when administered intracerebroventricularly. Alosetron, administered either centrally or peripherally, appears to modulate the visceral nociceptive effect of rectal distension in dogs.


FSS-2019-nCov: A deep learning architecture for semi-supervised few-shot segmentation of COVID-19 infection.
The newly discovered coronavirus (COVID-19) pneumonia is providing major challenges to research in terms of diagnosis and disease quantification. Deep-learning (DL) techniques allow extremely precise image segmentation; yet, they necessitate huge volumes of manually labeled data to be trained in a supervised manner. Few-Shot Learning (FSL) paradigms tackle this issue by learning a novel category from a small number of annotated instances. We present an innovative semi-supervised few-shot segmentation (FSS) approach for efficient segmentation of 2019-nCov infection (FSS-2019-nCov) from only a few amounts of annotated lung CT scans. The key challenge of this study is to provide accurate segmentation of COVID-19 infection from a limited number of annotated instances. For that purpose, we propose a novel dual-path deep-learning architecture for FSS. Every path contains encoder-decoder (E-D) architecture to extract high-level information while maintaining the channel information of COVID-19 CT slices. The E-D architecture primarily consists of three main modules: a feature encoder module, a context enrichment (CE) module, and a feature decoder module. We utilize the pre-trained ResNet34 as an encoder backbone for feature extraction. The CE module is designated by a newly introduced proposed Smoothed Atrous Convolution (SAC) block and Multi-scale Pyramid Pooling (MPP) block. The conditioner path takes the pairs of CT images and their labels as input and produces a relevant knowledge representation that is transferred to the segmentation path to be used to segment the new images. To enable effective collaboration between both paths, we propose an adaptive recombination and recalibration (RR) module that permits intensive knowledge exchange between paths with a trivial increase in computational complexity. The model is extended to multi-class labeling for various types of lung infections. This contribution overcomes the limitation of the lack of large numbers of COVID-19 CT scans. It also provides a general framework for lung disease diagnosis in limited data situations.


Anatomical MRI study of basal ganglia in major depressive disorder.
The basal ganglia form a part of the brain neuroanatomic circuits that may be involved in mood regulation. Decreases in basal ganglia volumes have been previously reported in major depressive disorder patients in comparison to healthy controls. In this study, we measured caudate, putamen, and globus pallidus volumes in 25 patients with major depressive disorder (4 M; age+/-S.D.=41+/-11 years) and 48 healthy controls (29 M; age+/-S.D.=35+/-10 years), using high-resolution magnetic resonance imaging (MRI), in an attempt to replicate prior findings. Unlike most previous studies, we did not find significant differences between patient and control groups in basal ganglia volumetric measures. Nonetheless, there was a significant interaction between diagnosis and cerebral hemisphere, with MDD patients showing decreased asymmetry in globus pallidus volumes in comparison with healthy controls. Furthermore, in the patient group, left putamen volumes correlated inversely with length of illness, and left globus pallidus volume correlated directly with number of prior depressive episodes. These findings suggest that abnormalities in lateralization and possibly neurodegenerative changes in basal ganglia structures participate in the pathophysiology of major depressive disorder.


High Seeding Density Induces Local Hypoxia and Triggers a Proinflammatory Response in Isolated Human Islets.
Hypoxia is the main threat to morphological and functional integrity of isolated pancreatic islets. Lack of oxygen seems to be of particular importance for functionality of encapsulated islets. The present study was initiated as an experimental model for the environment experienced by human islets in a confined space present during culture, shipment, and in an implanted macrodevice. Quadruplicate aliquots of isolated human islets (n = 12) were cultured for 24 h at 37°C under normoxic conditions using 24-well plates equipped with 8-µm pore size filter inserts and filled with islet aliquots adjusted to obtain a seeding density of 75, 150, 300, or 600 IEQ/cm(2). After culture viability, glucose-stimulated insulin release, DNA content as well as Bax and Bcl-2 gene expression were measured. Culture supernatants were collected to determine production of VEGF and MCP-1. Viability correlated inversely with IEQ seeding density (r = -0.71, p < 0.001), while the correlation of VEGF and MCP-1 secretion with seeding density was positive (r = 0.78, p < 0.001; r = 0.54, p < 0.001). Decreased viability corresponded with a significant increase in the Bax/Bcl-2 mRNA ratio at 300 and 600 IEQ/cm(2) and with a sigificantly reduced glucose-stimulated insulin secretion and insulin content compared to 75 or 150 IEQ/cm(2) (p < 0.01). The present study demonstrates that the seeding density is inversely correlated with islet viability and in vitro function. This is associated with a significant increase in VEGF and MCP-1 release suggesting a hypoxic and proinflammatory islet microenvironment.


Transnational labour migration and the politics of care in the Southeast Asian family.
Recent increases in female labour migration in and from Asia have triggered a surge of interest in how the absence of the mother and wife for extended periods of time affects the left-behind family, particularly children, in labour-sending countries. While migration studies in the region have shown that the extended family, especially female relatives, is often called on for support in childcare during the mother's absence it is not yet clear how childcare arrangements are made. Drawing on in-depth interviews with non-parent carers of left-behind children in Indonesia and Vietnam, the paper aims to unveil complexities and nuances around care in the context of transnational labour migration. In so doing it draws attention to the enduring influence of social norms on the organisation of family life when women are increasingly drawn into the global labour market. By contrasting a predominantly patrilineal East Asian family structure in Vietnam with what is often understood as a bilateral South-East Asian family structure in Indonesia, the paper seeks to provide interesting comparative insights into the adaptive strategies that the transnational family pursues in order to cope with the reproductive vacuum left behind by the migrant mother.


Hyperbaric oxygen therapy for traumatic brain injury: bench-to-bedside.
Traumatic brain injury (TBI) is a serious public health problem in the United States. Survivors of TBI are often left with significant cognitive, behavioral, and communicative disabilities. So far there is no effective treatment/intervention in the daily clinical practice for TBI patients. The protective effects of hyperbaric oxygen therapy (HBOT) have been proved in stroke; however, its efficiency in TBI remains controversial. In this review, we will summarize the results of HBOT in experimental and clinical TBI, elaborate the mechanisms, and bring out our current understanding and opinions for future studies.


Enhancing performance of subject-specific models via subject-independent information for SSVEP-based BCIs.
Recently, brain-computer interface (BCI) systems developed based on steady-state visual evoked potential (SSVEP) have attracted much attention due to their high information transfer rate (ITR) and increasing number of targets. However, SSVEP-based methods can be improved in terms of their accuracy and target detection time. We propose a new method based on canonical correlation analysis (CCA) to integrate subject-specific models and subject-independent information and enhance BCI performance. We propose to use training data of other subjects to optimize hyperparameters for CCA-based model of a specific subject. An ensemble version of the proposed method is also developed for a fair comparison with ensemble task-related component analysis (TRCA). The proposed method is compared with TRCA and extended CCA methods. A publicly available, 35-subject SSVEP benchmark dataset is used for comparison studies and performance is quantified by classification accuracy and ITR. The ITR of the proposed method is higher than those of TRCA and extended CCA. The proposed method outperforms extended CCA in all conditions and TRCA for time windows greater than 0.3 s. The proposed method also outperforms TRCA when there are limited training blocks and electrodes. This study illustrates that adding subject-independent information to subject-specific models can improve performance of SSVEP-based BCIs.


A Novel Recombinant Human Collagen-based Flowable Matrix for Chronic Lower Limb Wound Management: First Results of a Clinical Trial.
Chronic ulcers pose a significant health concern and economic burden. Numerous products, including animal-derived collagen products, have been designed to provide the injured site with a biocompatible structural matrix that promotes tissue regeneration. Yet, animal-derived collagens can evoke immune responses, bear risk of disease transmission, and fail to closely mimic the function of native collagen. This study aims to assess the safety and performance of a novel flowable wound matrix, formulated from tobacco plant-purified fibrillated recombinant human type I collagen (rhCollagen), in patients with chronic lower limb ulcers. This single-arm, open-label, multicenter trial took place at 5 treatment centers. Wounds were photographed and preliminary surgical debridement was performed prior to rhCollagen application. Patients received a single application of rhCollagen to the wound bed, followed by weekly assessments of the wound. Twenty patients (mean age, 63 years), presenting with a chronic ulcer of neuropathic (45%), posttraumatic (35%), postoperative (10%), and venous (10%) origin, underwent rhCollagen treatment. Initial wound area ranged between 0.2 cm3 to 9.2 cm3. At 4-weeks posttreatment, median wound area reduction was 94%. Fifteen ulcers exhibited ≥ 70% wound closure, 9 of which achieved complete closure. Only 1 participant suffered a local self-resolving wound infection. No significant device-related adverse events were reported throughout the study. A single, easy-to-use rhCollagen flowable gel application for chronic lower limb ulcers may promote wound closure with minimal adverse events.


If you don't take it - it can't work: the consequences of not being treated or nonadherence to osteoporosis therapy.
Osteoporosis is a growing problem worldwide, linked to an increasingly aging population. Despite the availability of a wide variety of treatments for osteoporosis, a significant number of patients are either not being prescribed treatment or discontinue therapy as early as 6 months after initiation. The reasons for a lack of adherence are many but poor adherence increases the risk of fracture and, therefore, the disease burden to the patient and society. Results from large-scale, randomized clinical studies have shown that different osteoporosis treatments are efficacious in reducing the risk of fracture. Studies assessing the effects of discontinuing osteoporosis therapies show that some treatments appear to continue to protect patients from the risk of future fracture even when treatment is stopped. However, these trials involve patients who have been compliant with treatment for between 2 and 5 years, a situation not reflective of real-world clinical practice. In reality, patients who discontinue therapy within the first 6 months may never achieve the optimum protection from fracture regardless of which treatment they have been prescribed. Clinicians need to develop management strategies to enable patients to adhere to their treatment. This will ultimately result in better prevention of fracture and a lower burden of disease to society and patients.


Of old and new diseases: genetics of pituitary ACTH excess (Cushing) and deficiency.
The pituitary gland orchestrates our endocrine environment: it produces hormones in response to hypothalamic factors that integrate neural inputs and its activity is balanced by the feedback action of peripheral hormones. Disruption of this equilibrium has severe consequences that affect multiple systems and may be fatal. Genetic analysis of pituitary function led to discovery of critical transcription factors that cause hormone deficiencies when mis-expressed. This review will summarize recent findings that led to the first complete clinical description of inherited, isolated corticotropin (ACTH) deficiency (IAD) and to the first molecular mechanism for excessive ACTH production in Cushing's disease. Indeed, mutations in TPIT, a positive or negative regulator of cell fates for different pituitary lineages, cause neonatal IAD, a condition considered anecdotic before discovery of this transcription factor. Cushing's disease is caused by corticotroph adenomas that produce excess ACTH as a result of resistance to glucocorticoids (Gc). Molecular investigation of the normal mechanism of Gc feedback led to identification of two essential proteins for pro-opiomelanocortin repression that are often mis-expressed in corticotroph adenomas thus providing a molecular explanation for Gc resistance. These two proteins, Brg1 and histone deacetylase 2 (HDAC2), are involved in chromatin remodeling and may also participate in the tumorigenic process, as Brg1 is a tumor suppressor. These recent advances have provided improved diagnosis and opened new perspectives for patient management and therapies.


Si-Mg isotopes in enstatite chondrites and accretion of reduced planetary bodies.
Among the primitive meteorite classes, Enstatite Chondrites (EC) are believed to share a common origin with the Earth due to its close similarity with terrestrial mantle (Bulk Silicate Earth, BSE) for numerous isotope systematics. Si isotopes are an exception to this trend and the large δ30Si difference of ~0.3‰ between bulk EC and BSE has been used to argue against any major contribution of EC like planetary materials in Earth's accretion. However, Si possess a bimodal distribution among silicate and metallic fractions of EC because of its formation under highly reducing conditions. Based on high precision Si isotope analyses in micro-milled phase separates of EH3 chondrites, here we report the presence of significantly light Si isotopes in EC-metals (δ30Si ≥ -6.94 ± 0.09‰, Mg/Si = ~0.001) whereas its silicate phases are isotopically heavier (Av. δ30SiEC-silicates = -0.33 ± 0.11‰, Mg/Si = ~1.01) and closer to BSE (δ30SiBSE = -0.29 ± 0.08‰). We discuss the origin of the observed Si isotope heterogeneity in terms of gas-solid interaction processes associated with metal-silicate condensation at high C/O environment (~0.83). Although the elevated δ30Si of BSE compared to chondrites is consistent with earlier conclusions that lighter Si has partitioned into Earth's metallic core, our results indicate that the super-chondritic Si isotope composition of BSE does not reflect the sole consequence of high temperature-pressure core and mantle equilibration in a deep magma-ocean. Instead, Si along with Mg isotope analyses carried out in the same aliquot of EC micro-phase separates suggest that processes such as metal-silicate Si isotope fractionation at reduced nebular environment and vapor loss of lighter Si isotopes during planetary volatilization were also influential in establishing the Si isotope composition of terrestrial mantle.


Axial strain calculation using a low-pass digital differentiator in ultrasound elastography.
In ultrasound elastography, tissue axial strains are calculated from the gradient of the estimated axial displacements. However, the common differentiation operation amplifies the noises in the displacement estimation, especially at high frequencies. In this paper, a low-pass digital differentiator (LPDD) is proposed to calculate the axial strain from the estimated tissue displacement. Several LPDDs that have been well developed in the field of digital signal processing are presented. The corresponding performances are compared qualitatively and quantitatively in computer simulations and in preliminary phantom and in vitro experiments. The results are consistent with the theoretical analysis of the LPDDs.


Biomarkers in active surveillance.
The use of active surveillance (AS) is increasing for favorable-risk prostate cancer. However, there remain challenges in patient selection for AS, due to the limitations of current clinical staging. In addition, monitoring protocols relying on serial biopsies is invasive and presents risks such as infection. For these reasons, there is substantial interest in identifying markers that can be used to improve AS selection and monitoring. In this article, we review the evidence on serum, urine and tissue markers in AS.


Expression, purification and characterization of B72.3 Fv fragments.
The Fv fragment of the antibody B72.3 has been produced by expression in both a mammalian and microbial system, namely Chinese hamster ovary (CHO) cells and Escherichia coli. In both cases secretion of the Fv into the culture medium was achieved, with equivalent amounts of Vh and Vl produced. The yield of Fv from CHO cells was 4 mg/l in roller-bottle culture. E. coli proved to be a more productive system with yields of 40 mg/l in shake flasks rising to 450 mg/l in fermentations. B72.3 Fv from both sources was capable of binding to antigen with similar binding ability to the Fab' fragment. A detailed sedimentation analysis, both by velocity and equilibrium techniques, revealed that the two domains of Fv are associated at high concentrations at pH values close to neutral, but dissociate at concentrations lower than approx. 0.5 mg/ml. Individual Vh or Vl polypeptides are not able to bind to the antigen and thus these results suggest that the antigen promotes assembly of Fv at the low concentrations used in the antigen-binding assays. At a pH value of 1.9, Vh and Vl are completely dissociated even at very high concentrations and are apparently unfolded at low solute concentrations. Small-angle X-ray scattering was used to measure a radius of gyration of 1.75 +/- 0.2 nm (17.5 +/- 2 A) for Fv.


Pathogen genomic surveillance of typhoidal Salmonella infection in adults and children reveals no association between clinical outcomes and infecting genotypes.
India is endemic for enteric fever, and it is not known whether the variations in clinical manifestations between patients are due to host, environmental or pathogen factors.Blood culture surveillance was conducted at St. John's Medical College Hospital, Bangalore, between July 2016 and June 2017. Clinical, laboratory and demographic data were collected from each case, and bacterial isolates were subjected to whole genome sequencing. Comparative analysis between adults and paediatric patients was carried out to ascertain differences between adult and paediatric disease. Among the 113 cases of blood culture-confirmed enteric fever, young adults (16-30 years) and children < 15 years accounted for 47% and 37% of cases, respectively. Anaemia on presentation was seen in 46% of cases, and 19% had an abnormal leucocyte count on presentation. The majority received treatment as inpatients (70%), and among these, adults had a significantly longer duration of admission when compared with children (p = 0.002). There were atypical presentations including arthritis, acute haemolysis and a case of repeated typhoid infection with two separate S. Typhi genotypes. There was no association between infecting genotype/serovar and treatment status (outpatient vs inpatient), month of isolation, duration of admission, patient age (adult or child), antimicrobial susceptibility, Widal positivity or haematologic parameters. Amidst the many public health concerns of South India, enteric fever continues to contribute substantially to hospital burden with non-specific as well as uncommon clinical features in both paediatric and adult populations likely driven by host and environmental factors. Robust clinical surveillance as well monitoring of pathogen population structure is required to inform treatment and preventive strategies.