Xylitol does not inhibit xylose fermentation by engineered Saccharomyces cerevisiae expressing xylA as severely as it inhibits xylose isomerase reaction in vitro.
Efficient fermentation of xylose, which is abundant in hydrolysates of lignocellulosic biomass, is essential for producing cellulosic biofuels economically. While heterologous expression of xylose isomerase in Saccharomyces cerevisiae has been proposed as a strategy to engineer this yeast for xylose fermentation, only a few xylose isomerase genes from fungi and bacteria have been functionally expressed in S. cerevisiae. We cloned two bacterial xylose isomerase genes from anaerobic bacteria (Bacteroides stercoris HJ-15 and Bifidobacterium longum MG1) and introduced them into S. cerevisiae. While the transformant with xylA from B. longum could not assimilate xylose, the transformant with xylA from B. stercoris was able to grow on xylose. This result suggests that the xylose isomerase (BsXI) from B. stercoris is functionally expressed in S. cerevisiae. The engineered S. cerevisiae strain with BsXI consumed xylose and produced ethanol with a good yield (0.31 g/g) under anaerobic conditions. Interestingly, significant amounts of xylitol (0.23 g xylitol/g xylose) were still accumulated during xylose fermentation even though the introduced BsXI might not cause redox imbalance. We investigated the potential inhibitory effects of the accumulated xylitol on xylose fermentation. Although xylitol inhibited in vitro BsXI activity significantly (K(I) = 5.1 ± 1.15 mM), only small decreases (less than 10%) in xylose consumption and ethanol production rates were observed when xylitol was added into the fermentation medium. These results suggest that xylitol accumulation does not inhibit xylose fermentation by engineered S. cerevisiae expressing xylA as severely as it inhibits the xylose isomerase reaction in vitro.


Women with larger breasts are less satisfied with their breasts: Implications for quality of life and physical activity participation.
Although low breast satisfaction has been associated with a range of potential negative health implications, little is known about key factors that influence breast satisfaction across the lifespan. This study aimed to determine the impacts of age, body mass and breast size on breast satisfaction and how breast satisfaction impacts psychosocial and sexual well-being-related quality of life outcomes and physical activity behaviours. Three hundred and forty-five women (age range: 18.1-83.7 years) had their body mass (kg), standing height (cm) and breast volume (ml) measured. A 13-item questionnaire comprising the Breast-Q and Active Australia Survey was used to assess breast satisfaction, quality of life outcomes and participation in physical activity. Breast satisfaction was influenced by breast size, such that women with larger breasts were less satisfied with their breasts compared to their counterparts with smaller breasts. Greater breast satisfaction was associated with improved psychosocial and sexual well-being-related measures of quality of life, and time spent participating in physical activity. Interventions to improve breast satisfaction among women across the breast size spectrum should be encouraged in public health initiatives to better engage and encourage positive health behaviours and reduce potential adverse health implications.


Needs, Perceptions and Education in Sarcoidosis: A Live Interactive Survey of Patients and Partners.
Sarcoidosis is a chronic, multisystem disease with often a major impact on quality of life. Information on unmet needs of patients and their partners is lacking. We assessed needs and perceptions of sarcoidosis patients and their partners. During patient information meetings in 2015 and 2017 in the Erasmus University Medical Center, we interviewed patients and partners using interactive voting boxes. Patients responded anonymously to 17 questions. Answers were projected directly on the screen in the room. 210 patients and 132 partners participated. Sarcoidosis has a subjective significant impact on lives of both patients and partners. The vast majority of patients and partners feel regularly misunderstood because of the general unawareness of sarcoidosis. Many patients and partners experience anxiety. Three-quarters of patients would like to see more attention and support for their psychological problems. Additionally, more supportive care for partners of sarcoidosis patients is warranted. Interactive interviewing was considered educational (91%) and pleasant (84%). This study improves awareness of needs and perceptions of patients with sarcoidosis and their partners. Sarcoidosis leads to anxiety and psychological distress and impairs well-being of patients and their partners. Attention for psychological support, better disease education, and more supportive care for partners is warranted.


Reliability of the Washington University Road Test. A performance-based assessment for drivers with dementia of the Alzheimer type.
To assess the reliability and stability of a standardized road test for healthy aging people and those with dementia of the Alzheimer type (DAT). A prospective study involving patients with DAT and age-matched healthy controls in which subjects' driving performance was evaluated by several raters in an initial and a follow-up road test. Urban medical school and urban highways and streets. A convenience sample of 58 controls, 36 subjects with very mild DAT, and 29 subjects with mild DAT. Analysis of road test ability of controls (2 subjects [3%] failed the test), very mild DAT subjects (7 subjects [19%] failed), and mild DAT subjects (12 subjects [41%] failed) disclosed a significant association between driving performance and dementia status (chi 2[4] = 20.65 [N = 123]; P < .001; Kendall tau-b = 0.306). Interrater reliability for assessment of driving performance ranged from kappa = 0.85 to 0.96. One-month test-retest stability on the road test was 0.76 (quantitative scoring) and 0.53 (clinical judgment). Dementia adversely affects driving performance even in its mild stages, although some persons with DAT seem to drive safely for some time after disease onset. A traffic-interactive, performance-based road test that examines cognitive behaviors provides an accurate and reliable functional assessment of driving ability.


Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma.
Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.


Stem cell factor binding to retrovirus primer binding site silencers.
Using modified nuclear lysis and binding conditions, we have examined the binding of an embryonal carcinoma (EC) cell factor, binding factor A, to a stem cell-specific silencer which acts at the DNA level and overlaps the Moloney murine leukemia virus (M-MuLV) proline primer binding site (PBS). Following our protocol, we found that in vitro binding of factor A correlated with the in vivo activity of the M-MuLV silencer. Factor A bound specifically to the wild-type silencer element at room temperature and 30 degrees C, but not at 4 degrees C, and bound 10-fold better to the full-length silencer than to a minimal silencer core element. The factor was enriched in nuclear compared with cytosolic extracts and in undifferentiated EC cells compared with differentiated cells in which the silencer is nonfunctional. Salt and ion requirements for factor A binding were investigated, and partial purification steps indicated the factor to be a heparin-Sepharose-binding moiety of greater than 100 kDa. To examine possible relationships between silencer and PBS activities, sequences representing phenylalanine, isoleucine, lysine-1,2, lysine-3, methionine, and tryptophan PBS DNA fragments were tested in vivo for stem cell-specific repression of M-MuLV expression and in vitro in DNA binding assays. Of these PBS elements, only the lysine-1,2 PBS DNA fragment showed consistently high levels of repression. Interestingly, the lysine-1,2 PBS DNA fragment also formed a complex with an EC cell factor with characteristics similar to those of factor A. However, the two factors did not cross-compete in binding studies, suggesting that they may be different but related factors. Our results suggest that expression of Mason-Pfizer monkey virus, visna virus, and spumavirus, which use the lysine-1,2 PBS, may be inhibited in undifferentiated stem cells.


Characteristics of patients with systemic sclerosis suffering from a lower limb amputation: Results of a French collaborative study.
Systemic sclerosis mainly affects the microvascular network. However, macrovascular manifestations have been reported. We aimed to investigate the characteristics of systemic sclerosis patients with an amputation of a lower limb segment. We designed a retrospective, case-control, multicentric study on systemic sclerosis patients with amputation of a lower limb segment secondary to critical ischemia via the French Research Group on Systemic Sclerosis. For each case, a control (systemic sclerosis patient without lower limb symptom) was matched with sex, age (±5 years), and cutaneous subset of systemic sclerosis. In total, 26 systemic sclerosis patients (mean age of 67.2 ± 10.9 years, 20 females, 21 limited cutaneous forms) with a lower limb amputation and 26 matched controls (mean age of 67.3 ± 11.2 years, 20 females, 22 limited cutaneous forms) were included. At the time of amputation, the mean disease duration was 12.8 (±8.6) years. In comparison to controls, systemic sclerosis patients with amputation had more digital ulcers (p = 0.048), history of digital ulcers (p = 0.026), and a higher prevalence of pulmonary arterial hypertension (p = 0.024). Systemic sclerosis patients with amputation were more often smokers (p = 0.008) and under corticosteroids (p = 0.015). In the multivariate model, pulmonary arterial hypertension, smoking status, and corticosteroids were independent markers associated with lower limb amputation in systemic sclerosis. In the follow-up, 10 patients (38.5%) had recurrent ischemia requiring a new limb amputation, and five patients (19.2%) had an amputation of the contralateral limb. This study identifies some markers associated with lower limb amputation in systemic sclerosis such as digital ulcers and pulmonary arterial hypertension and points out the high risk associated with tobacco consumption and corticosteroid use.


Inheritance of Resistance to Stagonospora nodorum Leaf Blotch in Kansas Winter Wheat Cultivars.
Stagonospora nodorum blotch can cause serious yield and quality losses of wheat (Triticum aestivum) in many countries worldwide. Although there are other control methods, host resistance is the most desirable. Three recent Kansas winter wheat cultivars (Betty, Heyne, and 2163) have been developed with moderate levels of resistance to the leaf phase of Stagonospora nodorum blotch. To determine inheritance of resistance and allelism, these cultivars were crossed with one of three susceptible lines (Larned, KS96WGRC39, or Newton) and intercrossed in all possible combinations, including reciprocals. The parents, F1, F2, and F3 generations were tested for resistance to S. nodorum in the greenhouse as 4-week-old seedlings. Cytoplasmic effects were not detected in any cross. The mean levels of infection in the F1s of the two crosses Betty × Larned and Heyne × KS96WGRC39 indicated resistance was dominant. The observed phenotypic ratios of F2 plants for both crosses were not significantly different from the expected ratio for a single dominant gene. The ratio observed for F3 lines in the Betty × Larned cross fit that expected for a single dominant gene. However, the observed ratio of the F3 lines from the cross Heyne × KS96WGRC39 did not fit the ratio expected for a single dominant gene. The allelism test for Betty and Heyne indicated that they have different resistance genes. The F1 mean rating of the cross 2163 × Newton was intermediate between the two parents, indicating the absence of dominance for resistance in 2163. The phenotypic ratio observed in the F2 plants from this cross did not fit the ratio expected for a single dominant gene. The simple genetic control of resistance in cv. Betty makes it a useful source of resistance for wheat breeding programs.


Imitating versus non-imitating movements: differences in frontal electroencephalographic oscillatory activity.
Non phase-locked oscillatory changes were studied in seven healthy volunteers during two different reaction time movement paradigms, in which the stimulus was a wrist movement (either extension or flexion) performed by another person seated in front of the subject (examiner). In the first paradigm (imitation), the subject was instructed to perform the same movement observed. In the second paradigm (non-imitation), the subject was instructed to perform the opposite movement (flexion when an extension was observed, and vice-versa). Changes in the 7-37 Hz range band were determined by means of Gabor transforms. A frontal energy increase (event-related synchronization, ERS) around 15 Hz could be observed in the frontal region after the examiner's movement; this frontal ERS was significantly larger in the non-imitation paradigm. A typical alpha and beta movement-related event-related desynchronization/synchronization (ERD/ERS) pattern was also observed in both paradigms in the central region. The beta-ERD was significantly larger in the imitation paradigm. Our results show that the motor preparation mechanisms involved in an imitated and a non-imitated movement are different.


Preformed frequencies of cytomegalovirus (CMV)-specific memory T and B cells identify protected CMV-sensitized individuals among seronegative kidney transplant recipients.
Cytomegalovirus (CMV) infection remains a major complication after kidney transplantation. Baseline CMV risk is typically determined by the serological presence of preformed CMV-specific immunoglobulin (Ig) G antibodies, even though T-cell responses to major viral antigens are crucial when controlling viral replication. Some IgG-seronegative patients who receive an IgG-seropositive allograft do not develop CMV infection despite not receiving prophylaxis. We hypothesized that a more precise evaluation of pretransplant CMV-specific immune-sensitization using the B and T-cell enzyme-linked immunospot assays may identify CMV-sensitized individuals more accurately, regardless of serological evidence of CMV-specific IgG titers. We compared the presence of preformed CMV-specific memory B and T cells in kidney transplant recipients between 43 CMV IgG-seronegative (sR(-)) and 86 CMV IgG-seropositive (sR(+)) patients. Clinical outcome was evaluated in both groups. All sR(+) patients showed a wide range of CMV-specific memory T- and B-cell responses. High memory T- and B-cell frequencies were also clearly detected in 30% of sR(-) patients, and those with high CMV-specific T-cell frequencies had a significantly lower incidence of late CMV infection after prophylactic therapy. Receiver operating characteristic curve analysis for predicting CMV viremia and disease showed a high area under the receiver operating characteristic curve (>0.8), which translated into a high sensitivity and negative predictive value of the test. Assessment of CMV-specific memory T- and B-cell responses before kidney transplantation among sR(-) recipients may help identify immunized individuals more precisely, being ultimately at lower risk for CMV infection.


Effects of timolol and betaxolol on choroidal blood flow in the rabbit.
This study evaluated the effects of the topical beta1-adrenergic antagonist betaxolol and the non-selective beta-adrenergic antagonist timolol on the choroidal pressure-flow relationship. Pentobarbital-anesthetized rabbits were instrumented with hydraulic occluders on the aorta and inferior vena cava to control MAP, an ear artery cannula to measure mean arterial pressure (MAP), and two vitreous cannulas to control and measure intraocular pressure (IOP). Choroidal blood flow was measured by laser Doppler flowmetry with the fiber-optic probe tip positioned over the posterior pole. Choroidal pressure-flow curves were obtained before and 30 min after topical application of 0.1 ml of betaxolol (Betoptic, 0.5%, n=10), timolol (Timoptic, 0.5%, n=10) or saline (n=8) by varying the MAP without controlling the IOP and by raising IOP while holding the MAP constant at 70 mmHg. The IOP was significantly reduced by betaxolol and timolol but not by saline. MAP was also slightly, but significantly, reduced after betaxolol but not after timolol or saline. However, the systemic hypotensive response to isoproterenol (8 microgram/kg, i.v.) was blunted after betaxolol and timolol indicating appreciable systemic absorption of both drugs. Timolol, but not betaxolol or saline, caused a significant, small increase in baseline choroidal vascular resistance. Timolol also attenuated the IOP response to MAP; however, none of the treatments had a significant effect on the choroidal pressure-flow relationship. We conclude that both drugs reach the systemic circulation after topical application, but neither betaxolol nor timolol alter the choroidal response to acute changes in perfusion pressure.


A STUDY OF THE PHYSIOLOGICAL ACTIVITY OF ADENOMATA OF THE THYROID GLAND, IN RELATION TO THEIR IODINE CONTENT, AS EVIDENCED BY FEEDING EXPERIMENTS ON TADPOLES.
It seems evident from the foregoing experiments that the so called tumors (adenomata) of the thyroid possess the property of taking up iodine and metabolizing it into the active combination in the same way that the non-tumorous thyroid tissue does, although not so readily nor to the same degree, and the action on tadpoles of feeding desiccated tumorous thyroid tissue does not differ qualitatively from feeding desiccated non-tumorous thyroid tissue. The action in either case depends upon the iodine (active iodine) content, and in the case of the adenomata bears no constant relation to the state of their growth or differentiation. Examination of Tables II and III shows that in the main this is true. There are, however, certain discrepancies as to time of death, appearance of first forelegs, degree of emaciation, and rate of growth in certain dishes of the series, the action being not quite parallel to the iodine content. Some of these discrepancies may be explained in part by accidents of feeding, slight differences in size, age) and susceptibility of the different tadpoles receiving the same thyroid, and also by the variations in the amount of thyroid consumed by the different individuals in the same dish. Lenhart has shown that the action of the same thyroid varies with the quantity fed. Another important factor which has to be considered is the condition of the iodine itself. It was suspected at the time of these experiments that the iodine might be present in an active and an inactive form, but no satisfactory proof of this assumption, at the beginning of these experiments, was at hand. Support of this point has been afforded by the work of Kendall on the isolation of the active principle of thyroid and the separation of the iodine into two fractions. Since the completion of our experiments Marine has demonstrated by means of perfusion experiments in vivo and in vitro that iodine is rapidly taken up by the thyroid cells, and though the iodine increase in the perfused lobe may be 1,000 per cent in 2 hours as compared with the control lobe, yet the action on tadpoles is no greater. It then becomes an important question to determine the time required by the thyroid to take up inorganic iodine and manufacture it into the active thyroid principle. It is known that iodine is rapidly taken up by the thyroid, and in man the iodine content of the thyroid is subject to greater variations than in animals on account of the prevalent therapeutic use of iodine and the iodides in goiter and other conditions; even the iodine used in preparing patients for operations would increase the iodine content of the thyroid in a short time, so that one might expect such variations in the action of a given thyroid preparation fed to tadpoles as appear in these experiments. In this connection it is interesting to note (Table II) that Thyroid 20 with 4.31 mg. of iodine was only slightly more active than No. 5 with 1.31 mg. of iodine. Two possibilities have to be considered here. First, No. 20 may have active iodine slightly greater than 1.31 mg. and the balance present as inactive iodine. Second, No. 5 with 1.31 mg. of iodine might represent the maximum possible effect under the conditions of the experiment and a larger quantity of active thyroid iodine could produce no greater effect. Of course with the lower iodine contents the variations in effects might well come within the limits of errors of observation. Also the percentage error would be greater in the iodine determinations, accidents of feeding, etc. Our conclusions as to the effect of feeding desiccated thyroid to tadpoles agree in general with those of Lenhart. The action of the thyroid depends not upon a specific stimulus to differentiation but upon a stimulation of metabolism in general in proportion to the active iodine and the quantity consumed. High iodine contents produce rapid emaciation, at the same time resulting in differentiation even in tadpoles dying in 8 to 12 days. Low iodine contents result in differentiation at an earlier period than the controls. Tadpoles fed on thyroid with practically no iodine grow better than the controls, in this instance the thyroid acting simply as a food. Finally, the interest that the results of these experiments may have in connection with the question of function in tumor tissue should be pointed out. To those who hold that tumor lacks the capacity for physiological function, the adenomata of the thyroid could not be consistently regarded as tumors. To those who hold physiological function as a possible property of tumor tissue, the adenomata might be regarded as tumors. Future studies might warrant a recognition of different grades or degrees of tumor. On this basis the fetal adenoma (very little differentiation) might represent a higher degree of tumor than the diffuse colloid or simple adenomatous thyroid in which the adenomatous nodules are present to a great extent throughout the whole gland and are well differentiated. It is certain that there are all grades and degrees of growth and differentiation in the life history of fetal adenomata of the thyroid, from the pure fetal, undifferentiated adenoma with little or no iodine to the simple or colloid adenoma, well differentiated and with varying amounts of iodine approaching that of normal thyroid.


A dynamic mucin mRNA signature associates with COVID-19 disease presentation and severity.
BACKGROUNDSARS-CoV-2 infection induces mucin overexpression, further promoting disease. Given that mucins are critical components of innate immunity, unraveling their expression profiles that dictate the course of disease could greatly enhance our understanding and management of COVID-19.METHODSUsing validated RT-PCR assays, we assessed mucin mRNA expression in the blood of patients with symptomatic COVID-19 compared with symptomatic patients without COVID-19 and healthy controls and correlated the data with clinical outcome parameters. Additionally, we analyzed mucin expression in mucus and lung tissue from patients with COVID-19 and investigated the effect of drugs for COVID-19 treatment on SARS-CoV-2-induced mucin expression in pulmonary epithelial cells.RESULTSWe identified a dynamic blood mucin mRNA signature that clearly distinguished patients with symptomatic COVID-19 from patients without COVID-19 based on expression of MUC1, MUC2, MUC4, MUC6, MUC13, MUC16, and MUC20 (AUCROC of 91.8%; sensitivity and specificity of 90.6% and 93.3%, respectively) and that discriminated between mild and critical COVID-19 based on the expression of MUC16, MUC20, and MUC21 (AUCROC of 89.1%; sensitivity and specificity of 90.0% and 85.7%, respectively). Differences in the transcriptional landscape of mucins in critical cases compared with mild cases identified associations with COVID-19 symptoms, respiratory support, organ failure, secondary infections, and mortality. Furthermore, we identified different mucins in the mucus and lung tissue of critically ill COVID-19 patients and showed the ability of baricitinib, tocilizumab, favipiravir, and remdesivir to suppress expression of SARS-CoV-2-induced mucins.CONCLUSIONThis multifaceted blood mucin mRNA signature showed the potential role of mucin profiling in diagnosing, estimating severity, and guiding treatment options in patients with COVID-19.FUNDINGThe Antwerp University Research and the Research Foundation Flanders COVID-19 funds.


Adventures in boron chemistry - the prediction of novel ultra-flexible boron oxide frameworks.
Recent periodic density functional calculations have predicted the existence of ultra-flexible low-energy forms of boron oxides in which rigid boron-oxygen heterocycles are linked by flexible B-O-B bridges. The minima in the energy landscapes of these frameworks are remarkably broad, with widths in excess of those of many hybrid metal-organic frameworks. Enormous changes in cell volume, which can exceed a factor of two, are accompanied by negligible changes in energy. Here we explore the underlying reasons for this behaviour using molecular electronic-structure calculations, periodic density functional theory and template-based geometric simulations. The angular flexibility of the B-O-B bridge depends only upon the geometry of the local B2O5 unit, independent of the configuration of neighbouring bridges. Unique cooperativity between the bending and twisting motions of the bridges leads to considerable anisotropy in framework flexibility. Exceptional flexibility is conferred not only by the intrinsic bending flexibility of the bridges but by topological factors, crucially the relaxation of torsional constraints when B3O3 rings are present. We test these conclusions by showing how the flexibility of the frameworks can be tuned by decoration with isoelectronic rings. The new nanoporous boron oxides presented in this work are predicted to be potential novel guest-host materials because of their flat energy landscapes. Furthermore, such structures can be generated systematically from silicates by the substitution of B2O54- for SiO44-. A borate analogue of β-cristobalite is shown to be isoenergetic with the known B2O3-I polymorph. We raise the possibility of new families of frameworks and zeolite analogues.


Suppression of near band edge emission in specially engineered ZnO twin nanorods.
We report the synthesis of a unique zinc oxide nanorod structure in which an amorphous ZnO layer is sandwiched between two identical crystalline segments of ZnO. A simple hydrothermal reaction method was used for this purpose, which allowed us to tune the amorphous and crystalline sections of the nanorods via reaction temperature. A systematic study of the morphology and dimensions of the nanorods grown under various conditions was performed using a combination of scanning and transmission electron microscopy. Transmission electron microscopy (TEM) clearly showed an amorphous separation between the two crystalline segments. UV-vis absorption spectroscopy of the twin nanorods (TNRs) showed a redshift in the optical band gap as a function of the growth duration, indicating slightly stressed growth of the crystalline segments. For a longer growth duration, as the amorphous gap starts to get bridged by crystalline growth, redshift in optical band gap becomes constant. This confirms a true mechanical gap between the two crystalline segments of the nanorods. Temperature dependent photoluminescence (PL) spectra of the TNRs showed a variation in free exciton (FX) emission energy, which fitted very well to a model incorporating lattice dilation in addition to the standard electron-phonon interactions. At low temperatures (below ∼180 K) we observed the appearance of visible emission peaks due to localization of defect levels. A loss in the near band edge emission intensity was observed at low temperatures, commensurate with the appearance of defect emission in the visible range.


Do non-targeted effects increase or decrease low dose risk in relation to the linear-non-threshold (LNT) model?
In this paper we review the evidence for departure from linearity for malignant and non-malignant disease and in the light of this assess likely mechanisms, and in particular the potential role for non-targeted effects. Excess cancer risks observed in the Japanese atomic bomb survivors and in many medically and occupationally exposed groups exposed at low or moderate doses are generally statistically compatible. For most cancer sites the dose-response in these groups is compatible with linearity over the range observed. The available data on biological mechanisms do not provide general support for the idea of a low dose threshold or hormesis. This large body of evidence does not suggest, indeed is not statistically compatible with, any very large threshold in dose for cancer, or with possible hormetic effects, and there is little evidence of the sorts of non-linearity in response implied by non-DNA-targeted effects. There are also excess risks of various types of non-malignant disease in the Japanese atomic bomb survivors and in other groups. In particular, elevated risks of cardiovascular disease, respiratory disease and digestive disease are observed in the A-bomb data. In contrast with cancer, there is much less consistency in the patterns of risk between the various exposed groups; for example, radiation-associated respiratory and digestive diseases have not been seen in these other (non-A-bomb) groups. Cardiovascular risks have been seen in many exposed populations, particularly in medically exposed groups, but in contrast with cancer there is much less consistency in risk between studies: risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, a cause-and-effect interpretation of the reported statistical associations for cardiovascular disease is unreliable but cannot be excluded. Inflammatory processes are the most likely mechanism by which radiation could modify the atherosclerotic disease process. If there is to be modification by low doses of ionizing radiation of cardiovascular disease through this mechanism, a role for non-DNA-targeted effects cannot be excluded.


Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)?
The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.


Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.
Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. Clinicaltrials.gov NCT00126672.


A qualitative study of pharmacists' perspectives on the supply of emergency hormonal contraception via patient group direction in the UK.
To investigate pharmacists' views and experiences of supplying emergency hormonal contraception (EHC) via a group prescribing protocol in community pharmacies in the UK. Qualitative study using depth interviews. Community pharmacists in Manchester, Salford and Trafford (Greater Manchester), and Lambeth, Southwark and Lewisham (London) Health Action Zones in the UK. Forty-four community pharmacists supplying EHC in Manchester, Salford and Trafford, and Lambeth, Southwark and Lewisham (London). Pharmacists were broadly very positive about their experiences supplying EHC via the group prescribing protocol. Pharmacists identified many benefits of the EHC schemes for clients, in particular, improved access to EHC at no cost to clients. The confidential nature of the scheme was also seen as an advantage as was the scope for referral to other service providers. Pharmacists also believed that the scheme had benefits for the profession in terms of enhanced professional standing. However, their concerns included the extent of repeated use of EHC, the possible impact on contraceptive behaviors and sexually transmitted infections and its impact on male coercive sexual behavior. Although pharmacy supply of EHC may improve access for some clients and is perceived as a popular service, research into the implications of the schemes as identified in this study need to be conducted.


Conifer R2R3-MYB transcription factors: sequence analyses and gene expression in wood-forming tissues of white spruce (Picea glauca).
Several members of the R2R3-MYB family of transcription factors act as regulators of lignin and phenylpropanoid metabolism during wood formation in angiosperm and gymnosperm plants. The angiosperm Arabidopsis has over one hundred R2R3-MYBs genes; however, only a few members of this family have been discovered in gymnosperms. We isolated and characterised full-length cDNAs encoding R2R3-MYB genes from the gymnosperms white spruce, Picea glauca (13 sequences), and loblolly pine, Pinus taeda L. (five sequences). Sequence similarities and phylogenetic analyses placed the spruce and pine sequences in diverse subgroups of the large R2R3-MYB family, although several of the sequences clustered closely together. We searched the highly variable C-terminal region of diverse plant MYBs for conserved amino acid sequences and identified 20 motifs in the spruce MYBs, nine of which have not previously been reported and three of which are specific to conifers. The number and length of the introns in spruce MYB genes varied significantly, but their positions were well conserved relative to angiosperm MYB genes. Quantitative RTPCR of MYB genes transcript abundance in root and stem tissues revealed diverse expression patterns; three MYB genes were preferentially expressed in secondary xylem, whereas others were preferentially expressed in phloem or were ubiquitous. The MYB genes expressed in xylem, and three others, were up-regulated in the compression wood of leaning trees within 76 hours of induction. Our survey of 18 conifer R2R3-MYB genes clearly showed a gene family structure similar to that of Arabidopsis. Three of the sequences are likely to play a role in lignin metabolism and/or wood formation in gymnosperm trees, including a close homolog of the loblolly pine PtMYB4, shown to regulate lignin biosynthesis in transgenic tobacco.


How family planning ideas are spread within social groups in rural Malawi.
Using data from in-depth interviews conducted between March and June 2002 in a rural district of Malawi, this study explores how family planning attitudes and practices spread among members of social groups. Gender differentials are found in how people determine other group members' practices: Men "knew" about such practices from their observations of others' family size and child spacing, whereas women's knowledge was based on their conversations with other women. The discussion topics relating to family planning also varied by sex: Men spoke about the pros and cons of limiting family size, whereas women spoke in detail about types of contraceptive methods, where to get them, their side effects, and covert contraceptive use. For men and women, the main trigger for family planning discussions was gossip. Whereas, generally, women first heard about family planning at the hospital, men stated that their first source of information was the radio or health-drama group.


HETEROTRANSPLANTATION OF THE KIDNEY: TWO CLINICAL EXPERIENCES.
The field of heterotransplantation is now being explored because of success with immunosuppressive measures in homotransplantation, and because of the scarcity of suitable human organs. Two patients in terminal uremia, maintained on dialysis, received heterotransplants from nonhuman primates. In the first case a renal heterotransplant from a rhesus monkey implanted in a 32-year old woman showed satisfactory immediate function but was removed after 10 days because of inadequate function. The second patient received a renal hetero transplant from a chimpanzee. A threatened rejection was reversed with immunosuppressive measures, but 2 months after transplantation the patient died of pneumonia. The transplanted kidneys showed no evidence of rejection.


Allied Health Clinicians' Understanding of Palliative Care as It Relates to Patients, Caregivers, and Health Clinicians: A Cross-Sectional Survey.
The scope of hospice or palliative care has expanded since its inception, which has significant ramifications for the AH workforce. This study sought to elicit allied health (AH) clinicians' understanding and views about palliative care and its relevance to their clinical practice and to identify their educational needs. Results from analysis of free text survey responses to a single open-ended question from a larger survey are presented. An online survey was distributed to AH clinicians via email lists for the CareSearch Allied Health Hub, Allied Health Professions Australia, and other groups. Descriptive statistics and content analysis of free text responses were used to analyse the data. A total of 217 AH clinicians responded to an email survey and 187 useable responses were analysed. Four themes were identified: 1) palliative care employs a client-centred model of care, 2) acknowledgement of living whilst dying, 3) interdisciplinary palliative care interventions provide active care in a range of domains, and 4) characteristics of palliative care teams and settings. AH clinicians plan an active role in physical, social, and psycho-spiritual care of palliative care patients and caregivers. Burgeoning numbers of palliative care patients in nonspecialist palliative care settings require AH clinicians to develop skills and competencies to work with people who have advanced disease.


Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells.
A c-Src inhibitor blocks oestrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing. Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodelling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.


DNA demethylases target promoter transposable elements to positively regulate stress responsive genes in Arabidopsis.
DNA demethylases regulate DNA methylation levels in eukaryotes. Arabidopsis encodes four DNA demethylases, DEMETER (DME), REPRESSOR OF SILENCING 1 (ROS1), DEMETER-LIKE 2 (DML2), and DML3. While DME is involved in maternal specific gene expression during seed development, the biological function of the remaining DNA demethylases remains unclear. We show that ROS1, DML2, and DML3 play a role in fungal disease resistance in Arabidopsis. A triple DNA demethylase mutant, rdd (ros1 dml2 dml3), shows increased susceptibility to the fungal pathogen Fusarium oxysporum. We identify 348 genes differentially expressed in rdd relative to wild type, and a significant proportion of these genes are downregulated in rdd and have functions in stress response, suggesting that DNA demethylases maintain or positively regulate the expression of stress response genes required for F. oxysporum resistance. The rdd-downregulated stress response genes are enriched for short transposable element sequences in their promoters. Many of these transposable elements and their surrounding sequences show localized DNA methylation changes in rdd, and a general reduction in CHH methylation, suggesting that RNA-directed DNA methylation (RdDM), responsible for CHH methylation, may participate in DNA demethylase-mediated regulation of stress response genes. Many of the rdd-downregulated stress response genes are downregulated in the RdDM mutants nrpd1 and nrpe1, and the RdDM mutants nrpe1 and ago4 show enhanced susceptibility to F. oxysporum infection. Our results suggest that a primary function of DNA demethylases in plants is to regulate the expression of stress response genes by targeting promoter transposable element sequences.


Treatments for shoulder impingement syndrome: a PRISMA systematic review and network meta-analysis.
Many treatments for shoulder impingement syndrome (SIS) are available in clinical practice; some of which have already been compared with other treatments by various investigators. However, a comprehensive treatment comparison is lacking. Several widely used electronic databases were searched for eligible studies. The outcome measurements were the pain score and the Constant-Murley score (CMS). Direct comparisons were performed using the conventional pair-wise meta-analysis method, while a network meta-analysis based on the Bayesian model was used to calculate the results of all potentially possible comparisons and rank probabilities. Included in the meta-analysis procedure were 33 randomized controlled trials involving 2300 patients. Good agreement was demonstrated between the results of the pair-wise meta-analyses and the network meta-analyses. Regarding nonoperative treatments, with respect to the pain score, combined treatments composed of exercise and other therapies tended to yield better effects than single-intervention therapies. Localized drug injections that were combined with exercise showed better treatment effects than any other treatments, whereas worse effects were observed when such injections were used alone. Regarding the CMS, most combined treatments based on exercise also demonstrated better effects than exercise alone. Regarding surgical treatments, according to the pain score and the CMS, arthroscopic subacromial decompression (ASD) together with treatments derived from it, such as ASD combined with radiofrequency and arthroscopic bursectomy, showed better effects than open subacromial decompression (OSD) and OSD combined with the injection of platelet-leukocyte gel. Exercise therapy also demonstrated good performance. Results for inconsistency, sensitivity analysis, and meta-regression all supported the robustness and reliability of these network meta-analyses. Exercise and other exercise-based therapies, such as kinesio taping, specific exercises, and acupuncture, are ideal treatments for patients at an early stage of SIS. However, low-level laser therapy and the localized injection of nonsteroidal anti-inflammatory drugs are not recommended. For patients who have a long-term disease course, operative treatments may be considered, with standard ASD surgery preferred over arthroscopic bursectomy and the open surgical technique for subacromial decompression. Notwithstanding, the choice of surgery should be made cautiously because similar outcomes may also be achieved by the implementation of exercise therapy.


Informed consent for functional MRI research on comatose patients following severe brain injury: balancing the social benefits of research against patient autonomy.
Functional MRI shows promise as a candidate prognostication method in acutely comatose patients following severe brain injury. However, further research is needed before this technique becomes appropriate for clinical practice. Drawing on a clinical case, we investigate the process of obtaining informed consent for this kind of research and identify four ethical issues. After describing each issue, we propose potential solutions which would make a patient's participation in research compatible with her rights and interests. First, we defend the need for traditional proxy consent against two alternative approaches. Second, we examine the impact of the intensive care unit environment on the informed consent process. Third, we discuss the therapeutic misconception and its potential influence on informed consent. Finally, we deal with issues of timing in recruiting participants and related factors which may affect the risks of participation.


Coordinated expression of galectin-3 and caveolin-1 in thyroid cancer.
Galectin-3 (Gal3) is the single most accurate marker for the diagnosis of differentiated thyroid cancer (DTC). Gal3 overrides the tumour suppressor activity of caveolin-1 (Cav1) and functions in concert with Cav1 to promote focal adhesion turnover and tumour cell migration and invasion. To study their coordinated role in progression of a human cancer, we investigated the expression of Gal3 and Cav1 in specimens of human benign thyroid lesions, DTC and anaplastic thyroid cancer (ATC). Gal3 and Cav1 expression is significantly associated with DTC and ATC, but not benign nodules. Essentially all Cav1-positive DTC cancers express Gal3, supporting the synergistic activity of these two proteins in DTC progression. Similarly, coordinated elevated Gal3/Cav1 expression was observed in three DTC-derived cell lines (papillary TCP1 and KTC1 and follicular FTC133) but only one (ACT1) of five ATC-derived cell lines. Using siRNA knockdown, Gal3 and Cav1 were shown to be required for RhoA GTPase activation, stabilization of focal adhesion kinase (FAK; a measure of focal adhesion signalling and turnover) and increased migration of the DTC cell lines studied, but not the ATC cell lines, including ACT1, which expresses elevated levels of Gal3 and Cav1. Co-expression of Gal3 and Cav1 in the T238 anaplastic cell line stabilized FAK-GFP in focal adhesions. Gal3 and Cav1 therefore function synergistically to promote focal adhesion signalling, migration and progression of DTC.


A cell membrane-anchored fluorescent probe for monitoring carbon monoxide release from living cells.
Carbon monoxide (CO) acts as an important gasotransmitter in delivering intramolecular and intermolecular signals to regulate a variety of physiological processes. This lipid-soluble gas can freely pass through the cell membrane and then diffuse to adjacent cells acting as a messenger. Although many fluorescent probes have been reported to detect intracellular CO, it is still a challenge to visualize the release behavior of endogenous CO. The main obstacle is the lack of a probe that can anchor onto the cell membrane while having the ability to image CO in real time. In this work, by grafting a polar head onto a long and linear hydrophobic Nile Red molecule, a cell membrane-anchored fluorophore ANR was developed. This design strategy of a cell membrane-anchored probe is simpler than the traditional one of using a long hydrophobic alkyl chain as a membrane-anchoring group, and endows the probe with better water solubility. ANR could rapidly bind to the cell membrane (within 1 min) and displayed a long retention time. ANR was then converted to a CO-responsive fluorescent probe (ANRP) by complexation with palladium based on a metal palladium-catalyzed reaction. ANRP exhibited a fast response to CO with a 25-fold fluorescence enhancement in vitro. The detection limit was calculated to be 0.23 μM, indicating that ANRP is sensitive enough to image endogenous CO. Notably, ANRP showed excellent cell membrane-anchoring ability. With ANRP, the release of CO from HepG2 cells under LPS- and heme-stimulated conditions was visualized and the cell self-protection effect during a drug-induced hepatotoxicity process was also studied. Moreover, ANRP was successfully applied to the detection of intracellular CO in several cell lines and tissues, and the results demonstrated that the liver is the main organ for CO production, and that cancer cells release more CO from their cells than normal cells. ANRP is the first membrane-anchored CO fluorescent probe that has the ability to reveal the relationship between CO release and diseases. It also has prospects for the studying of intercellular signaling functions of CO.


Magnetic Resonance Imaging-targeted Biopsy Versus Systematic Biopsy in the Detection of Prostate Cancer: A Systematic Review and Meta-analysis.
Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-TB) may be an alternative to systematic biopsy for diagnosing prostate cancer. The primary aims of this systematic review and meta-analysis were to compare the detection rates of clinically significant and clinically insignificant cancer by MRI-TB with those by systematic biopsy in men undergoing prostate biopsy to identify prostate cancer. A literature search was conducted using the PubMed, Embase, Web of Science, Cochrane library, and Clinicaltrials.gov databases. We included prospective and retrospective paired studies where the index test was MRI-TB and the comparator test was systematic biopsy. We also included randomised controlled trials (RCTs) if one arm included MRI-TB and another arm included systematic biopsy. The risk of bias was assessed using a modified Quality Assessment of Diagnostic Accuracy Studies-2 checklist. In addition, the Cochrane risk of bias 2.0 tool was used for RCTs. We included 68 studies with a paired design and eight RCTs, comprising a total of 14709 men who either received both MRI-TB and systematic biopsy, or were randomised to receive one of the tests. MRI-TB detected more men with clinically significant cancer than systematic biopsy (detection ratio [DR] 1.16 [95% confidence interval {CI} 1.09-1.24], p<0.0001) and fewer men with clinically insignificant cancer than systematic biopsy (DR 0.66 [95% CI 0.57-0.76], p<0.0001). The proportion of cores positive for cancer was greater for MRI-TB than for systematic biopsy (relative risk 3.17 [95% CI 2.82-3.56], p<0.0001). MRI-TB is an attractive alternative diagnostic strategy to systematic biopsy. We evaluated the published literature, comparing two methods of diagnosing prostate cancer. We found that biopsies targeted to suspicious areas on magnetic resonance imaging were better at detecting prostate cancer that needs to be treated and avoiding the diagnosis of disease that does not need treatment than the traditional systematic biopsy.


Singleton and twin confinements associated with infertility treatments.
A cross-sectional sample of 150 singleton and 159 twin confinements delivered in Western Australia in 1991 were randomly sampled in 1993; 63% of the women responded to a postal questionnaire. Thirteen percent of respondents with singletons and 26% of those with twins reported having problems conceiving at some stage in their life. Six percent of those who had singleton confinements and 22% of those women who had twin confinements sought fertility advice prior to the conception of the index pregnancy. One percent (95% CI 0.03%, 5.5%) of women with singletons received infertility treatment compared with 17% (95% CI 10.4%, 26.3%) of those with twins. Overall 82.7% (95% CI 75.2%, 90.1%) of twin confinements followed spontaneous conception, 11.2% (95% CI 5.7%, 19.2%) followed ovarian stimulation treatment alone and 6.1% (95% CI 2.3%, 12.9%) followed IVF or GIFT procedures. The probability of a spontaneous twin confinement was 1 in 95. It was concluded that nearly twice as many twin pregnancies were associated with ovarian stimulation treatment given alone than with IVF and GIFT combined. The routinely collected data about assisted twin conceptions provide an incomplete picture with regard to the role of different infertility treatment modalities.


Will the emergent SARS-CoV2 B.1.1.7 lineage affect molecular diagnosis of COVID-19?
As the coronavirus disease 2019 pandemic keep tackling global public health systems worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) genome keeps mutating. In that regard, the recent emergence of the B.1.1.7 lineage in the UK has called the attention of global authorities. One point of concern is that if this lineage can be detected by traditional molecular schemes for SARS-CoV-2 detection. Herein, we showed that this lineage does not affect the Berlin-Charité protocol but can challenge the available commercial kits directed to the Spike (S) gene. All efforts should be made to continue to monitor SARS-CoV-2 genomes for potential variants that can impair diagnostic testing and lead to false negative results.


Variability of chest pain in suspected acute myocardial infarction according to subjective assessment and requirement of narcotic analgesics.
In 653 patients with suspected acute myocardial infarction the course of pain according to subjective assessment and morphine requirement is described. Patients were asked to score pain from 0-10 until a pain-free interval of 12 hours appeared. Different categories of patients constructed from clinical aspects were compared. Although the variability between groups was fairly small, subgroups were found in which the initial intensity of pain was more marked and the duration of pain was longer. Thus patients with larger infarcts according to maximum serum enzyme activity and patients with Q-wave infarction had more severe pain initially and also a longer duration and a higher morphine requirement compared with patients with a lower serum enzyme activity or a non-Q-wave infarction. Other groups with a more severe course of chest pain were those with more intensive pain at home, electrocardiographic signs of acute myocardial infarction on admission to hospital, and finally those with a high systolic blood pressure or a high rate-pressure product on admission to the Coronary Care Unit. We thus conclude that there is a variability of chest pain in suspected acute myocardial infarction and that there are defined groups of patients in which a more severe course of chest pain could be expected.


Statistics of the contrast of coherent images.
Contrast optimization, also known as image sharpening, is a method that can be used to estimate phase errors in coherent images. However, the contrast measure of a coherent image is a random variable because of the speckle present in coherent images. The variance of this measure puts a limit on the ability of contrast optimization to focus an image. We derive the probability distribution function of the most common contrast measure, the sum of the pixel intensities raised to a power. These statistics are then verified by a number of speckle simulations and compared with measured statistics from synthetic aperture sonar images. The developed statistics can be used as a tool to understand and improve the method of contrast optimization as well as assess its performance for a given imaging system. They can also be used to predict the effect of certain image processing operations on the contrast.


A high-throughput screening method to identify small molecule inhibitors of thyroid hormone receptor coactivator binding.
To provide alternative methods for regulation of gene transcription initiated by the binding of thyroid hormone (T3) to the thyroid receptor (TR), we have developed a high-throughput method for discovering inhibitors of the interaction of TR with its transcriptional coactivators. The screening method is based on fluorescence polarization (FP), one of the most sensitive and robust high-throughput methods for the study of protein-protein interactions. A fluorescently labeled coactivator is excited by polarized light. The emitted polarized light is a function of the molecular properties of the labeled coactivator, especially Brownian molecular rotation, which is very sensitive to changes in the molecular mass of the labeled complex. Dissociation of hormone receptor from fluorescently labeled coactivator peptide in the presence of small molecules can be detected by this competition method, and the assay can be performed in a high-throughput screening format. Hit compounds identified by this method are evaluated by several secondary assay methods, including a dose-response analysis, a semiquantitative glutathione-S-transferase assay, and a hormone displacement assay. Subsequent in vitro transcription assays can detect inhibition of thyroid signaling at low micromolar concentrations of small molecules in the presence of T3.


Mapping quantitative trait loci in inbred backcross lines of Lycopersicon pimpinellifolium (LA1589).
Although tomato has been the subject of extensive quantitative trait loci (QTLs) mapping experiments, most of this work has been conducted on transient populations (e.g., F2 or backcross) and few homozygous, permanent mapping populations are available. To help remedy this situation, we have developed a set of inbred backcross lines (IBLs) from the interspecific cross between Lycopersicon esculentum cv. E6203 and L. pimpinellifolium (LA1589). A total of 170 BC2F1 plants were selfed for five generations to create a set of homozygous BC2F6 lines by single-seed descent. These lines were then genotyped for 127 marker loci covering the entire tomato genome. These IBLs were evaluated for 22 quantitative traits. In all, 71 significant QTLs were identified, 15% (11/71) of which mapped to the same chromosomal positions as QTLs identified in earlier studies using the same cross. For 48% (34/71) of the detected QTLs, the wild allele was associated with improved agronomic performance. A number of new QTLs were identified including several of significant agronomic importance for tomato production: fruit shape, firmness, fruit color, scar size, seed and flower number, leaf curliness, plant growth, fertility, and flowering time. To improve the utility of the IBL population, a subset of 100 lines giving the most uniform genome coverage and map resolution was selected using a randomized greedy algorithm as implemented in the software package MapPop (http://www.bio.unc.edu/faculty/vision/lab/ mappop/). The map, phenotypic data, and seeds for the IBL population are publicly available (http://soldb.cit.cornell.edu) and will provide tomato geneticists and breeders with a genetic resource for mapping, gene discovery, and breeding.


Videovoice: community assessment in post-Katrina New Orleans.
This study describes a videovoice project implemented in post-Katrina New Orleans during a pivotal time in city rebuilding and revitalization. Videovoice is a health advocacy, promotion, and research method through which people get behind video cameras to research issues of concern, communicate their knowledge, and advocate for change. Using videovoice method, a community-academic-filmmaker partnership engaged 10 Central City neighbors, who took part in an 18-week training and community assessment. The resulting 22-min film premiered before more than 200 city leaders and residents, reached more than 4,000 YouTube viewers during its first 2 months online, and was shared through the distribution of 1,000 DVDs. Viewing further helped mobilize the community for action on three priority issues: affordable housing, education, and economic development. Challenges in using videovoice, including privacy issues and cost considerations in a resource-poor community, are discussed. Despite such challenges, this method may provide community-academic partnerships with the opportunity to equitably engage in research, produce independent media, and mobilize for action.


Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis.
For more than 40 y, expression of HLA-B27 has been strongly associated with the chronic inflammatory disease Ankylosing Spondylitis (AS); however, the mechanisms underlying this association are still unknown. Single nucleotide polymorphisms within the aminopeptidase endoplasmic reticulum aminopeptidase 1 (ERAP1), which is essential for trimming peptides before they are presented to T cells by major histocompatibility complex (MHC) class I molecules, have been linked with disease. We show that ERAP1 is a highly polymorphic molecule comprising allotypes of single nucleotide polymorphisms. The prevalence of specific ERAP1 allotypes is different between AS cases and controls. Both chromosomal copies of ERAP1 are codominantly expressed, and analysis of allotype pairs provided clear stratification of individuals with AS versus controls. Functional analyses demonstrated that ERAP1 allotype pairs seen in AS cases were poor at generating optimal peptide ligands for binding to murine H-2K(b) and -D(b) and the AS-associated HLA-B*2705. We therefore provide strong evidence that polymorphic ERAP1 alters protein function predisposing an individual to AS via its influence on the antigen processing pathway.


Axl as a mediator of cellular growth and survival.
The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context.


Rescripting early memories linked to negative images in social phobia: a pilot study.
Negative self-images are a maintaining factor in social phobia. A retrospective study (Hackmann, A., Clark, D.M., McManus, F. (2000). Recurrent images and early memories in social phobia. Behaviour Research and Therapy, 38, 601-610) suggested that the images may be linked to early memories of unpleasant social experiences. This preliminary study assessed the therapeutic impact of rescripting such memories. Patients with social phobia (N=11) attended 2 sessions, 1 week apart. The first was a control session in which their images and memories were discussed but not modified. The second was an experimental session in which cognitive restructuring followed by an imagery with rescripting procedure was used to contextualize and update the memories. No change was observed after the control session. The experimental session led to significant improvement in negative beliefs, image and memory distress and vividness, fear of negative evaluation, and anxiety in feared social situations. The results suggest that rescripting unpleasant memories linked to negative self-images may be a useful adjunct in the treatment of social phobia.


Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites.
Selective ion conduction across ion channel pores is central to cellular physiology. To understand the underlying principles of ion selectivity in tetrameric cation channels, we engineered a set of cation channel pores based on the nonselective NaK channel and determined their structures to high resolution. These structures showcase an ensemble of selectivity filters with a various number of contiguous ion binding sites ranging from 2 to 4, with each individual site maintaining a geometry and ligand environment virtually identical to that of equivalent sites in K(+) channel selectivity filters. Combined with single channel electrophysiology, we show that only the channel with four ion binding sites is K(+) selective, whereas those with two or three are nonselective and permeate Na(+) and K(+) equally well. These observations strongly suggest that the number of contiguous ion binding sites in a single file is the key determinant of the channel's selectivity properties and the presence of four sites in K(+) channels is essential for highly selective and efficient permeation of K(+) ions.


The effect of alterations of schizophrenia-associated genes on gamma band oscillations.
Abnormalities in the synchronized oscillatory activity of neurons in general and, specifically in the gamma band, might play a crucial role in the pathophysiology of schizophrenia. While these changes in oscillatory activity have traditionally been linked to alterations at the synaptic level, we demonstrate here, using computational modeling, that common genetic variants of ion channels can contribute strongly to this effect. Our model of primary auditory cortex highlights multiple schizophrenia-associated genetic variants that reduce gamma power in an auditory steady-state response task. Furthermore, we show that combinations of several of these schizophrenia-associated variants can produce similar effects as the more traditionally considered synaptic changes. Overall, our study provides a mechanistic link between schizophrenia-associated common genetic variants, as identified by genome-wide association studies, and one of the most robust neurophysiological endophenotypes of schizophrenia.


Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis.
Octreotide long-acting repeatable (LAR) is indicated for the treatment of carcinoid syndrome and diarrhea related to VIPoma, and may delay tumor growth in patients with neuroendocrine tumors (NETs). To the authors' knowledge, the pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well documented. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors identified patients with NET aged ≥ 65 years who were diagnosed between July 1999 and December 2007. Patients with US Food and Drug Administration-approved indications for octreotide LAR were identified from Medicare claims. Multivariate logistic regression was performed to ascertain factors associated with octreotide LAR use, whereas the Cox proportional hazards model was used to evaluate the impact of octreotide LAR on survival. Among those with Food and Drug Administration-approved indications, 245 of 4848 patients with distant-stage disease (51%) and 81 of 807 patients with local/regional disease (10%) initiated treatment with octreotide LAR within 6 months of diagnosis. Multivariate logistic regression indicated that among those with distant-stage disease, older age (≥ 80 years vs 65-69 years) (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.23-0.81), female sex (OR, 0.62; 95% CI, 0.40-0.97), and living in the South (vs Northeast) (OR, 0.36; 95% CI, 0.18-0.72) were associated with a lower likelihood of using octreotide LAR. The multivariate proportional hazards model showed that octreotide LAR provided a significant 5-year survival benefit for patients with distant-stage disease (hazards ratio, 0.61; P ≤ .001), whereas this survival benefit was not shown for the patients with local/regional stage (hazards ratio, 0.88; P = .563). The results of this retrospective study suggest a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The results of the current study also suggest that octreotide LAR is underused in this population despite recommended guidelines.


In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivatives.
The aim of this study was to synthesise and determine the transdermal penetration of cytarabine alkylamide derivatives and assess the correlation of flux with physicochemical properties. The alkylamide derivatives of cytarabine were synthesised by acylation at the N4-amino group by the mixed anhydride method. The in-vitro permeation studies were performed using the Franz diffusion cell methodology. Furthermore, partition coefficients (n-octanol-water) and aqueous solubility of the N4-alkylamide derivatives of cytarabine were determined in order to obtain information about their lipophilicity and hydrophilicity. The N4-alkylamides of cytarabine (acetyl, butanoyl, hexanoyl, octanoyl, and decanoyl derivatives) showed decreased hydrophilicity and increased lipophilicity. The log D values of the alkylamides were higher than that of the parent compound and increased linearly as the alkyl chain lengthened. N4-hexanoyl-4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl] pyrimidin-2-one) showed the highest median steady-state flux (J(ss)) of 89.0 nmol/cm(2) per h in the series, which shows a high statistical difference with the parent compound flux value (3.70 nmol/cm(2) per h). The prodrug approach appears to be a promising strategy for the enhancement of transdermal penetration of cytarabine.


First Report of Apple mosaic virus in Alaska.
Apple mosaic virus (ApMV; family Bromoviridae, genus Ilarvirus) is one of the oldest and most economically important viruses of apples (Malus × domestica Borkh.) (1,3). Yield losses may vary from negligible to as much as 50%, depending on the affected cultivar. Although ApMV is found worldwide and occurs naturally in more than 65 plant species (1), it has not been reported to occur in Alaska. In July 2011, noticeably bright yellow mosaic leaves were observed on apple 'Valentine' and its rootstalk 'Ranetka' from an apple orchard in Wasilla, AK. Leaves were collected and assayed by reverse transcription (RT)-PCR using ApMV-specific primers (2) and total RNA extracted with buffer modifications to RNeasy Plant Mini Kit (Qiagen, Valencia, CA). Briefly, 50 mg of leaf tissue was ground in liquid nitrogen and 450 μl of SE buffer (0.14 M NaCl, 2 mM KCl, 2 mM KH2PO4, 8 mM Na2HPO4·2H2O [pH 7.4], 0.05% vol/vol Tween-20, 2% wt/vol polyvinylpyrrolidone 40, 0.2% wt/vol ovalbumin, 0.5% wt/vol bovine serum albumin, and 0.05% wt/vol sodium azide) was added, and after vigorous vortexing, 80 μl of the mixture was added to 400 μl of RLT buffer supplied by the kit and then processed as directed by the manufacturer (4). Direct sequencing of the predicted ~260-bp PCR product resulted in 97 to 98% nucleotide identities to ApMV accessions in GenBank when analyzed by BLAST. To determine the distribution and incidence of infection in the Wasilla orchard, all 118 apple trees (99 cultivars) were then sampled and assayed serologically by double-antibody sandwich-ELISA with ApMV antiserum according to the manufacturer's protocol (Agdia, Inc., Elkhart, IN). Apple 'Geneva Early' and the same 'Valentine' tree and its rootstock tested positive for ApMV by ELISA and RT-PCR. Strong diagnostic ApMV symptoms were not apparent on the infected 'Geneva Early', which is typical for most commercially grown apples. No leaves were available on the 'Ranetka' rootstock of ApMV-infected 'Geneva Early' for virus indexing. An additional 21 apple trees with no symptoms from an orchard in Talkeetna, AK tested negative to ApMV by ELISA. Limited natural spread of ApMV to other plants may be by pollen and seed transmission. The most prevalent mode of transmission is from ApMV-infected rootstock and grafts. It is important to obtain new propagation plant material from certified virus tested nurseries and to avoid grafting plant material containing ApMV. To my knowledge, this is the first report of ApMV in Alaska. References: (1) R. W. Fulton. No. 83. CMI/AAB Descriptions of Plant Viruses. 1972. (2) W. Menzel et al. J. Virol. Methods 99:81, 2002. (3) M. J. Roossinck et al. Virus Taxonomy. Eight Report of the International Committee on Taxonomy of Viruses, 1049, 2005. (4) J. Thompson et al. J. Virol. Methods 111:85, 2003.


Health financing for the poor produces promising short-term effects on utilization and out-of-pocket expenditure: evidence from Vietnam.
Vietnam introduced the Health Care Fund for the Poor in 2002 to increase access to health care and reduce the financial burden of health expenditure faced by the poor and ethnic minorities. It is often argued that effects of financing reforms take a long time to materialize. This study evaluates the short-term impact of the program to determine if pro-poor financing programs can achieve immediate effects on health care utilization and out-of-pocket expenditure. Considering that the program is a non-random policy initiative rolled out nationally, we apply propensity score matching with both single differences and double differences to data from the Vietnam Household Living Standards Surveys 2002 (pre-program data) and 2004 (first post-program data). We find a small, positive impact on overall health care utilization. We find evidence of two substitution effects: from private to public providers and from primary to secondary and tertiary level care. Finally, we find a strong negative impact on out-of-pocket health expenditure. The results indicate that the Health Care Fund for the Poor is meeting its objectives of increasing utilization and reducing out-of-pocket expenditure for the program's target population, despite numerous administrative problems resulting in delayed and only partial implementation in most provinces. The main lessons for low and middle-income countries from Vietnam's early experiences with the Health Care Fund for the Poor are that it managed to achieve positive outcomes in a short time-period, the need to ensure adequate and sustained funding for targeted programs, including marginal administrative costs, develop effective targeting mechanisms and systems for informing beneficiaries and providers about the program, respond to the increased demand for health care generated by the program, address indirect costs of health care utilization, and establish and maintain routine and systematic monitoring and evaluation mechanisms.


Mouse submaxillary renin: a useful model for the study of renal renin.
The submaxillary gland of mouse contains a renin-like enzyme which represents as much as 5% of the total protein content. Its physico-chemical and enzymatic characteristics are similar to those of renal renin. Recently, the amino-acid sequence of the submaxillary pre-prorenin molecule has been deduced from the nucleotide sequence of the renin structural gene. A model for pre-prorenin processing into active renin has been proposed. Comparison of the structures of mouse submaxillary renin and of aspartyl proteases shows that renin belongs to this class of proteins and shares a similar catalytic site. Although the structure of renal renin is not yet known, preliminary studies suggest that the renal pro-enzyme is processed as the submaxillary enzyme. However, glycosylation would occur in the case of renal renin, whereas submaxillary renin is not glycosylated. Genetic studies and DNA hybridization experiments in mouse with high or low renin content in the submaxillary gland show that submaxillary renin in high renin producing strains results from a gene duplication. Submaxillary renin is therefore an isoenzyme and a useful model for the study of renal renin.


An animal-specific FSI model of the abdominal aorta in anesthetized mice.
Recent research has revealed that angiotensin II-induced abdominal aortic aneurysm in mice can be related to medial ruptures occurring in the vicinity of abdominal side branches. Nevertheless a thorough understanding of the biomechanics near abdominal side branches in mice is lacking. In the current work we present a mouse-specific fluid-structure interaction (FSI) model of the abdominal aorta in ApoE(-/-) mice that incorporates in vivo stresses. The aortic geometry was based on contrast-enhanced in vivo micro-CT images, while aortic flow boundary conditions and material model parameters were based on in vivo high-frequency ultrasound. Flow waveforms predicted by FSI simulations corresponded better to in vivo measurements than those from CFD simulations. Peak-systolic principal stresses at the inner and outer aortic wall were locally increased caudal to the celiac and left lateral to the celiac and mesenteric arteries. Interestingly, these were also the locations at which a tear in the tunica media had been observed in previous work on angiotensin II-infused mice. Our preliminary results therefore suggest that local biomechanics play an important role in the pathophysiology of branch-related ruptures in angiotensin-II infused mice. More elaborate follow-up research is needed to demonstrate the role of biomechanics and mechanobiology in a longitudinal setting.


The non-display of authentic distress: public-private dualism in young people's discursive construction of self-harm.
This article draws from focus groups and interviews investigating how young people talk about self-harm. Some of the research participants had personal experience of self-harm but this was not a prerequisite for their inclusion in the study. Thematic coding was used initially to organise and give an overview of the data, but the data were subsequently analysed using a discourse analytic approach. The article focuses on the young people's constructions of deliberate self-harm such as 'cutting'. Throughout the focus groups and interviews, a dichotomy was set up by the young people between authentic, private self-harm which is rooted in real distress (and warrants a sympathetic response) and public, self-indulgent attempts to seek attention. This dualistic construction is discussed in some detail and located in various socio-cultural contexts. It is argued that the dualism illustrates contemporary ambivalence about mental health and youth.


Origins of lymphatic and distant metastases in human colorectal cancer.
The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. One prevailing model to explain this association posits that fatal, distant metastases are seeded by lymph node metastases. This view provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. Here we examine the evolutionary relationship between primary tumor, lymph node, and distant metastases in human colorectal cancer. Studying 213 archival biopsy samples from 17 patients, we used somatic variants in hypermutable DNA regions to reconstruct high-confidence phylogenetic trees. We found that in 65% of cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35% of cases they shared common subclonal origin. Therefore, two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer.


Factors influencing time to computed tomography in emergency department patients with suspected subarachnoid haemorrhage.
CT has excellent sensitivity for subarachnoid haemorrhage (SAH) when performed within 6 hours of headache onset, but it is unknown to what extent patients with more severe disease are likely to undergo earlier CT, potentially inflating estimates of sensitivity. Our objective was to evaluate which patient and hospital factors were associated with earlier neuroimaging in alert, neurologically intact ED patients with suspected SAH. We analysed data from two large sequential prospective cohorts of ED patients with acute headache undergoing CT for suspected SAH. We examined the time interval from headache onset to CT, both overall and subdivided from headache onset to hospital registration and from registration to CT. Among 2412 patients with headache, 194 had SAH, with 178 identified on unenhanced CT. Of these, 91 (51.1%) were identified by CT within 6 hours of headache onset and 87 after 6 hours. Patients with SAH had a shorter time from headache onset to hospital presentation (median 4.5 hours, IQR 1.7-22.7 vs 9.6 hours, IQR 2.8-46.0, p<0.001) and were imaged sooner after headache onset (6.4 hours, IQR 3.5-27.1 vs 12.6 hours, IQR 5.5-48.0, p<0.001) compared with those without SAH. The median time from in-hospital registration to CT scan was significantly shorter in those patients with SAH although this difference was less than 1 hour (1.9 hours, IQR 1.2-2.8 vs 2.5 hours, IQR 1.5-3.9, p<0.001). Arrival by ambulance (OR 3.1, 95% CI 1.94 to 4.98, p<0.001) and higher acuity at triage (OR 1.39, 95% CI 1.02 to 1.88, p=0.032) were among the factors associated with having CT imaging within 6 hours of headache onset. Time from headache onset to imaging is moderately associated with positive imaging for SAH. Delay to hospital presentation accounts for the largest fraction of time to imaging, especially those without SAH. These findings suggest limited opportunity to reduce lumbar puncture rates simply by accelerating in-hospital processes when imaging delays are under 2 hours, as diagnostic yield of imaging decreases beyond the 6-hour imaging window from headache onset.


Increasing burden of melanoma in the United States.
It is controversial whether worldwide increases in melanoma incidence represent a true epidemic. Dramatic increases in incidence in the setting of relatively stable mortality trends have also been attributed to expanded skin screening and detection of biologically indolent tumors with low metastatic potential. To better understand how melanoma incidence trends varied by severity at diagnosis and factors relevant to screening access, we assessed recent United States incidence and mortality trends by histologic type, tumor thickness, and area-level socioeconomic status (SES). We obtained population-based data regarding diagnoses of invasive melanoma among non-Hispanic whites from nearly 291 million person-years of observation by the Surveillance Epidemiology and End Results (SEER) program (1992-2004). Age-adjusted incidence and mortality rates were calculated for SEER and a subset (California) for which small-area SES measure was available. Overall, melanoma incidence increased at 3.1% (P<0.001) per year. Statistically significant rises occurred for tumors of all histologic subtypes and thicknesses, including those >4 mm. Melanoma incidence rates doubled in all SES groups over a 10-year period whereas melanoma mortality rates did not increase significantly. We conclude that screening-associated diagnosis of thinner melanomas cannot explain the increasing rates of thicker melanomas among low SES populations with poorer access to screening.


Clinical Assessment and Management of Spondyloarthritides in the Middle East: A Multinational Investigation.
Data on spondyloarthritis (SpA) from the Middle East are sparse and the management of these diseases in this area of the world faces a number of challenges, including the relevant resources to enable early diagnosis and referral and sufficient funds to aid the most appropriate treatment strategy. The objective was to report on the characteristics, disease burden, and treatment of SpA in the Middle East region and to highlight where management strategies could be improved, with the overall aim of achieving better patient outcomes. This multicenter, observational, cross-sectional study collected demographic, clinical, laboratory, and treatment data on 169 consecutive SpA patients at four centers (Egypt, Kuwait, Qatar, and Saudi Arabia). The data collected presents the average time from symptom onset to diagnosis along with the presence of comorbidities in the region and comparisons between treatment with NSAIDs and biologics. In the absence of regional registries of SpA patients, the data presented here provide a rare snapshot of the characteristics, disease burden, and treatment of these patients, highlighting the management challenges in the region.


Advanced technology development for remote triage applications in bleeding combat casualties.
Combat developers within the Army have envisioned development of a "wear-and-forget" physiological status monitor (PSM) that will enhance far forward capabilities for assessment of Warrior readiness for battle, as well as for remote triage, diagnosis and decision-making once Soldiers are injured. This paper will review recent work testing remote triage system prototypes in both the laboratory and during field exercises. Current PSM prototypes measure the electrocardiogram and respiration, but we have shown that information derived from these measurements alone will not be suited for specific, accurate triage of combat injuries. Because of this, we have suggested that development of a capability to provide a metric of circulating blood volume status is required for remote triage. Recently, volume status has been successfully modeled using low-level physiological signals obtained from wearable devices as input to machine-learning algorithms; these algorithms are already able to discriminate between a state of physical activity (common in combat) and that of central hypovolemia, and thus show promise for use in wearable remote triage devices.


CD4 T cells in tumor immunity.
T cell immunity is the key to protective immune responses against tumors. Traditionally, this function has been ascribed to CD8 T lymphocytes with cytotoxic activity, which are restricted by MHC class I molecules. In recent years the realization that CD4 T cells can also play a relevant role in protective anti-tumor responses has received growing attention. Here we will discuss the role of MHC class II-restricted T cells in response to, and in the regulation of, tumor antigens. Emphasis will be placed on four areas: (1) the role of CD4 T cell immunity in tumor protection in animal models and putative mode of action, (2) tumor antigens recognized by human CD4 T cells, (3) the cooperation between two CD4 T cells of different specificity as a new way to jump start the response against sub-immunogenic determinants of tumor antigens in a tolerant environment, and (4) the negative impact of regulatory CD4 T cells on anti-tumor T cell responses. By drawing attention to these four areas, it is our intention to provide the reader with a comprehensive view of issues of contemporary importance for this field, in the expectation that the information will help a better design of therapeutic cancer vaccines.


Cross-Pathway and Pathway-Specific Control of Amino Acid Biosynthesis in Magnaporthe grisea
The gene encoding the small subunit of the arginine-specific carbamoyl phosphate synthetase, ARG2, of Magnaporthe grisea was characterized to examine the basic regulation of biosynthetic genes in this plant pathogen. The transcript of the ARG2 gene contains an upstream open reading frame (uORF) that is similar to uORFs found in the homologous genes of Neurospora crassa (arg-2) and Saccharomyces cerevisiae (CPA1), suggesting that the M. grisea gene is translationally regulated by a mechanism that is conserved in these fungi. Amino acid imbalance leads to elevated levels of ARG2 mRNA, indicating that in addition to translational control, ARG2 is subject to cross-pathway transcriptional control. A DNA-binding activity that has properties similar to those of the global transcriptional regulator mediating cross-pathway control in N. crassa was detected in M. grisea cell extracts. Thus, it appears that both specific regulation of ARG2 by arginine and global regulation of amino acid biosynthesis are present in M. grisea and highly conserved among M. grisea, N. crassa, and S. cerevisiae.


Risk of Wrong-Patient Orders Among Multiple vs Singleton Births in the Neonatal Intensive Care Units of 2 Integrated Health Care Systems.
Multiple-birth infants in neonatal intensive care units (NICUs) have nearly identical patient identifiers and may be at greater risk of wrong-patient order errors compared with singleton-birth infants. To assess the risk of wrong-patient orders among multiple-birth infants and singletons receiving care in the NICU and to examine the proportion of wrong-patient orders between multiple-birth infants and siblings (intrafamilial errors) and between multiple-birth infants and nonsiblings (extrafamilial errors). A retrospective cohort study was conducted in 6 NICUs of 2 large, integrated health care systems in New York City that used distinct temporary names for newborns per the requirements of The Joint Commission. Data were collected from 4 NICUs at New York-Presbyterian Hospital from January 1, 2012, to December 31, 2015, and 2 NICUs at Montefiore Health System from July 1, 2013, to June 30, 2015. Data were analyzed from May 1, 2017, to December 31, 2017. All infants in the 6 NICUs for whom electronic orders were placed during the study periods were included. Wrong-patient electronic orders were identified using the Wrong-Patient Retract-and-Reorder (RAR) Measure. This measure was used to detect RAR events, which are defined as 1 or more orders placed for a patient that are retracted (ie, canceled) by the same clinician within 10 minutes, then reordered by the same clinician for a different patient within the next 10 minutes. A total of 10 819 infants were included: 85.5% were singleton-birth infants and 14.5% were multiple-birth infants (male, 55.8%; female, 44.2%). The overall wrong-patient order rate was significantly higher among multiple-birth infants than among singleton-birth infants (66.0 vs 41.7 RAR events per 100 000 orders, respectively; adjusted odds ratio, 1.75; 95% CI, 1.39-2.20; P < .001). The rate of extrafamilial RAR events among multiple-birth infants (36.1 per 100 000 orders) was similar to that of singleton-birth infants (41.7 per 100 000 orders). The excess risk among multiple-birth infants (29.9 per 100 000 orders) appears to be owing to intrafamilial RAR events. The risk increased as the number of siblings receiving care in the NICU increased; a wrong-patient order error occurred in 1 in 7 sets of twin births and in 1 in 3 sets of higher-order multiple births. This study suggests that multiple-birth status in the NICU is associated with significantly increased risk of wrong-patient orders compared with singleton-birth status. This excess risk appears to be owing to misidentification between siblings. These results suggest that a distinct naming convention as required by The Joint Commission may provide insufficient protection against identification errors among multiple-birth infants. Strategies to reduce this risk include using given names at birth, changing from temporary to given names when available, and encouraging parents to select names for multiple births before they are born when acceptable to families.


Early experience with balloon brachytherapy for breast cancer.
Partial-breast irradiation for carcinoma by a single source of radiation placed in the center of a balloon inserted in the lumpectomy cavity is an effective method of treating breast cancer. Previous interstitial radiation therapy using iridium seeds placed within multiple catheters has been shown to be effective but impractical and cosmetically unacceptable to women. Prospective registry study. Three university and community hospitals. Women 40 years and older with histologically diagnosed in situ and invasive T1 through T2 and N0 or N1 breast cancer treated with lumpectomy and axillary node sampling were invited to enter this institutional review board-approved study. Evaluation of immediate and short-term complications, patients' acceptance of the treatment, and cosmesis are reported. Of the 129 eligible patients enrolled, 112 completed the treatment. Of these, transient skin erythema was noted in 28, localized edema in 3, and skin blisters adjacent to the balloon in 9. Infection developed in 7, necessitating drainage and antibiotic administration. In 10 patients, sonographically demonstrated seromas that developed after removal of the device were aspirated percutaneously. In 4 patients, punctured or ruptured balloons had to be replaced before the treatment could be completed. Patients quickly adjusted to the breast distension caused by the balloon, and their acceptance of the procedure was good. The cosmetic outcome was rated high. There were no recurrences during this very short follow-up. Our early short-term experience indicates balloon brachytherapy to be an acceptable alternative to external beam radiation for selected operable breast cancers. The 1-week treatment time allows working women and those who live at a distance from radiation centers to choose breast conservation rather than mastectomy.