A comparison of chest radiographic findings in human immunodeficiency virus-positive and -negative children with pulmonary tuberculosis.
To compare chest radiography (CXR) findings in human immunodeficiency virus (HIV)-positive and HIV-negative children who had microbiologically confirmed pulmonary tuberculosis (PTB). Retrospective analysis of CXRs from children with known HIV status and microbiologically confirmed PTB (culture or GeneXpert Xpert MTB/RIF positive), who were hospitalised or seen at a primary healthcare centre over a 5-year period. Radiological findings were compared according to HIV and nutritional status. CXRs of 130 children were analysed from 35 (27%) HIV- positive and 95 (73%) HIV-negative children with confirmed PTB, median age 45.7 months (interquartile range [IQR] 18-81.3 months). CXR changes consistent with PTB were reported in 21/35 (60%) of HIV-positive and 59/95 (62%) of HIV-negative patients, (p=0.81). Normal CXR was identified in 3/35 (8.6%) of HIV-positive and 5/95 (5.3%) of HIV-negative patients (p=0.81). Airway compression was present in 3/35 (8.6%) of HIV-positive and 7/95 (7.4%) of HIV-negative patients (p>0.99). Overall, lymphadenopathy was identified in 42/130 (32.3%) of patients, 11/35 (31.4 %) were HIV-positive compared with 31/95 (32.6%) HIV-negative patients. Airspace consolidation was present in 60% of both HIV-positive (21/35) and HIV-negative patients (57/95). Pleural effusion was present in 2/35 (5.7 %) of HIV-negative and 9/95 (9.5 %) of HIV-negative patients. There were no statistically significant radiological differences by HIV group. There were no significant differences in the CXR findings between the HIV-positive and HIV-negative children with confirmed PTB.


A case of cutaneous T cell pseudolymphoma in a patient with Helicobacter pylori infection.
Cutaneous pseudolymphomas (CPL) are benign cutaneous lymphoproliferative infiltrations of various origin, including among others bacterial infections, viral infections and drugs . Helicobacter pylori has been frequently founded in the stomach of patients with MALT lymphoma. In January 2001, a 43-year-old man was referred to our department because of a 1-month history of itchy erythematous patches, plaques and flat tumors on his body. Histological examination revealed nodular infiltrations composed of lymphocytes, plasma cells and histiocytes with exocytosis of lymphocytes within the epidermis. Molecular analysis of rearrangement of T cell receptor and immunoglobulin heavy-chain genes did not reveal monoclonality. Based on these clinical, laboratory and histopathological data, a diagnosis of cutaneous T cell pseudolymphoma (CTPL) was made. The patient was anti-H. pylori antibody-positive, and was treated with anti-H. pylori combination with the result that all of the tumors had disappeared by January 2002. The patient has maintained complete response up to the last follow-up visit in December 2005.


Defects in resting metabolic rates and mitochondrial respiration in Kwashiorkor and dietary obese rats.
Resting metabolic rates have been measured and compared with hepatic mitochondrial respiration in Kwashiorkor and diet-induced obese weaned rats. In Kwashiorkor, resting metabolic rate was 21% lower than the value of controls, while that of the obese rats was 14% higher than in control animals. The resting metabolic rate for Kwashiorkor animals was 50% of the predicted basal metabolic rate (BMR), whereas that of the obese rats was 23% higher than the predicted BMR. The mitochondrial oxygen consumption patterns, using malate plus glutamate or succinate as respiratory substrates, revealed that the resting respiration (state 4) was 23.9% higher in Kwashiorkor and 29.1% higher in obese animals, while the active (state 3) respiration was 34.8% lower in Kwashiorkor and 43.3% lower in obese rats compared to controls. The respiratory control ratios (RCR) were 51.1% and 43.8% in Kwashiorkor and obese rats, respectively, relative to the values in control rats. It is concluded from these studies that Kwashiorkor disease and diet-induced obesity appear to interfere with oxygen utilization at the level of state 3 mitochondrial respiration, which is markedly decreased when compared to the values for control animals.


Facultative primary sex ratio variation: a lack of evidence in birds?
The facultative control of primary sex ratio by breeding birds has become a major focus in evolutionary biology in recent years. A combination of well-developed theoretical literature and rapid publication of empirical results has created considerable confusion, with controversial claims for both extreme control of primary sex ratio versus no control around inherent random variability. We present a robust and quantitative summary of published empirical literature to assess clearly the body of evidence for female birds to control sex assignment in their offspring. Our meta-analytical approach reveals that published studies do not exhibit any variability beyond that which could be expected owing to sampling error. Therefore, we conclude that facultative control of offspring sex is not a characteristic biological phenomenon in breeding birds.


Comment: 'Section 47'.
The use of the powers of compulsory removal contained in Section 47 of the 1948 National Assistance Act is reviewed. It is concluded that the powers are not seriously abused but that there is a need for their amendment. It is argued that any amendment should take the role of the consultant in geriatric medicine into consideration as the role of Medical officer of Health in whom these powers were vested has changed greatly since 1948.


Therapy of chronic delta hepatitis with interferon alfa-2b.
In this pilot study, 12 patients with chronic delta hepatitis were studied. The diagnosis was based on the presence of antibodies to the hepatitis delta antigen in the serum and hepatitis delta virus RNA and hepatitis delta antigen in the serum and liver. All patients were also positive for hepatitis B surface antigen. The infection was presumed to have been transmitted by intravenous drug abuse in six of the patients, blood transfusion in one and by sexual contact in four (two had antibodies to human immunodeficiency virus in their serum, but did not show signs of acquired immunodeficiency syndrome). In one further patient, the source of infection was unknown. Interferon alfa-2b (INTRON A, Schering-Plough Corporation) was initiated at 5 million units per day subcutaneously for at least 4 months, being reduced by half if side effects occurred. Serum alanine aminotransferase levels, hepatitis delta virus RNA and hepatitis delta antigen were measured at monthly intervals for up to 12 months in some patients. Interferon therapy resulted in decreased serum levels of these three markers. On cessation of therapy, most patients experienced a relapse over 6 months, but alanine amino transferase levels could be normalized once more by restarting interferon therapy. In conclusion, interferon decreased hepatic inflammation by the inhibition of hepatitis delta virus replication, although relapse occurred when interferon was stopped and long-term therapy is required to achieve permanent control of the disease. Care will be required when treating patients with advanced or decompensated liver disease.


Preliminary data using computed tomography texture analysis for the classification of hypervascular liver lesions: generation of a predictive model on the basis of quantitative spatial frequency measurements--a work in progress.
Computed tomography texture analysis (CTTA) is a method of quantifying lesion heterogeneity based on distribution of pixel intensities within a region of interest. This study investigates the ability of CTTA to distinguish different hypervascular liver lesions and compares CTTA parameters by creating a proof-of-concept model to distinguish between different lesions. Following institutional review board approval, CTTA software (TexRAD Ltd) was used to retrospectively analyze 17 cases of focal nodular hyperplasia, 19 hepatic adenomas, 25 hepatocellular carcinomas, and 19 cases of normal liver parenchyma using arterial phase scans. Two radiologists read the same image series used by the CTTA software and reported their best guess diagnosis. Computed tomography texture analysis parameters were computed from regions of interest using spatial band-pass filters to quantify heterogeneity. Random-forest method was used to construct a predictive model from these parameters, and a separate regression model was created using a subset of parameters. The random-forest model successfully distinguished the 3 lesion types and normal liver with predicted classification performance accuracy for 91.2% for adenoma, 94.4% for focal nodular hyperplasia, and 98.6% for hepatocellular carcinoma. This error prediction was generated using a subset of data points not used in generation of the model, but not on discrete prospective cases. In contrast, the 2 human readers using the same image series data analyzed by the CTTA software had lower accuracies, of 72.2% and 65.6%, respectively. The explicit regression model with a subset of image parameters had intermediate overall accuracy of 84.9%. Computed tomography texture analysis may prove valuable in lesion characterization. Differentiation between common hypervascular lesion types could be aided by the judicious incorporation of texture parameters into clinical analysis.


Hitting the ground running: Healthgrid deployment and adoption.
We consider the issues of healthgrid development, deployment and adoption in health care and research environments. While healthgrid technology could be deployed to support advanced medical research, we are not seeing its wide adoption. Understanding why this technology is not being exploited is one purpose of this paper. We do so in light of the seminal Healthgrid White Paper and the SHARE roadmap. We also address barriers to adoption and successes by presenting experiences in North America and Europe. By critically appraising where we are, we hope that we can hit the ground running in the near future.


Lymphatic drainage between thorax and abdomen: please take good care of this well-performing machinery….
Patients with sepsis often receive large amounts of fluids and the presence of capillary leak, trauma or bleeding results in ongoing fluid resuscitation. This increases interstitial and intestinal edema and finally leads to intra-abdominal hypertension (IAH), which in turn impedes lymphatic drainage. Patients with IAH often develop secondary respiratory failure needing mechanical ventilation with high intrathoracic pressure or PEEP that might further alter lymphatic drainage. This review will try to convince the reader of the importance of the lymphatics in septic patients with IAH. A Medline and PubMed literature search was performed using the terms "abdominal pressure", "lymphatic drainage" and "ascites formation". The references from these studies were searched for relevant articles that may have been missed in the primary search. These articles served as the basis for the recommendations below. Induction of sepsis with lesion of the capillary alveolar barrier results in an increased water gradient between the capillaries and the interstitium in the lungs. The drainage flow to the thoracic duct is initially increased in order to protect the lung and maintain the pulmonary interstitium as dry as possible, however this results in increased intrathoracic pressure. Sepsis also increases the permeability of the capillaries in the splanchnic beds. In analogy to the lungs the lymphatic flow in the splanchnic areas increases together with the pressure inside as a physiological response in order to limit the increase in IAP. At a critical IAP level (around 20 cmH2O) the lymph flow starts to decrease and the splanchnic water content progressively increases. The lymph flow from the abdomen to the thorax is progressively decreased resulting in increased splanchnic water content and ascites formation. The presence of mechanical ventilation with high PEEP reduces the lymph drainage further which together with the increase in IAP decreases the lymphatic pressure gradient in the splanchnic regions, with a further increase in water content and IAP triggering a vicious cycle. Although often overlooked the role of lymphatic flow is complex but very important to determine not only the fluid balance in the lung but also in the peripheral organs. Different pathologies and treatments can markedly influence the pathophysiology of the lymphatics with dramatic effects on endorgan function.


A conditional expectation approach for associating ambient air pollutant exposures with health outcomes.
Our research focuses on the association between exposure to an airborne pollutant and counts of emergency department visits attributed to a specific chronic illness. The motivating example for this analysis of measurement error in time series studies of air pollution and acute health outcomes was a study of emergency department visits from a 20-county Atlanta metropolitan statistical area from 1993-1999. The research presented illustrates the impact of using various surrogates for unobserved measurements of ambient concentrations at the zip code level. Simulation results indicate that the impact of measurement error on the association between pollutant exposure and a health outcome can be substantial. The proposed conditional expectation approach provided reliable estimates of the association and exhibited good confidence interval coverage for a variety of magnitudes of association. Use of a single-centrally located monitor, the arithmetic average, the nearest-neighbor monitor, and the inverse-distance weighted average surrogates resulted in biased estimates and poor coverage rates, especially for larger magnitudes of the association. A focus on obtaining reasonable exposure measurements within clearly defined subregions is important when the pollutant exposure of interest exhibits strong spatial variability.


Physical Activity Guidelines for the Brazilian Population: Recommendations Report.
This article presents the recommendations from the Physical Activity Guidelines for the Brazilian Population. A steering committee composed of a chair, 6 experts in physical activity, and representatives from the Ministry of Health/Brazil, Pan American Health Organization, Brazilian Society of Physical Activity and Health designed the guidelines, which was implemented by 8 working groups, as follows: (1) understanding physical activity, (2) children up to 5 years old, (3) children and youth from 6 to 17 years old, (4) adults, (5) older adults (60 years and above), (6) physical education at school, (7) pregnant and postpartum women, and (8) people with disabilities. The methodological steps included evidence syntheses, hearings with key stakeholders, and public consultation. Across 8 chapters, the guidelines provide definitions of physical activity and sedentary behavior, informing target groups on types of physical activity, dosage (frequency, intensity, and duration), benefits, and supporting network for physical activity adoption. The guidelines are openly available in Portuguese, Spanish, English, and Braille and in audio versions, with a supplementary guide for health professionals and decision makers, and a report about the preparation and references. The Physical Activity Guidelines for the Brazilian Population provide evidence-based recommendations, being a public-directed resource to contribute to the physical activity promotion in Brazil.


Chromatographic quantitation of plasma and erythrocyte pentosidine in diabetic and uremic subjects.
Pentosidine is a fluorescent advanced Maillard/glycosylation product and protein cross-link present in elevated amounts in skin from diabetic and uremic subjects. A high-performance liquid chromatographic (HPLC) assay was developed to quantitate pentosidine in plasma and erythrocytes and other tissue proteins with low levels of pentosidine. High protein content and presence of basic amino acids and O2 during acid hydrolysis led to the formation of fluorescent artifacts that could be separated from true pentosidine through combined reverse-phase ion-exchange HPLC. No true pentosidine was formed during acid hydrolysis of ribated protein, suggesting that Amadori products do not generate artifactual pentosidine during hydrolysis. With the combined reverse-phase ion-exchange chromatographic assay, we found a 2.5-fold (P less than 0.001) and a 23-fold (P less than 0.001) elevation of mean +/- SD plasma protein pentosidine in diabetic (2.4 +/- 1.2 pmol/mg) and uremic (21.5 +/- 10.8 pmol/mg) subjects compared with healthy (0.95 +/- 0.33 pmol/mg) subjects. Pentosidine in hemolysate was normal in diabetes but dramatically elevated in uremia (0.6 +/- 0.4 pmol/mg hemoglobin, P less than 0.001). Although the precise nature of the pentosidine precursor sugar is unknown, plasma pentosidine may be a useful marker for monitoring the biochemical efficacy of trials with aminoguanidine or other treatment modalities. Furthermore, pentosidine in plasma proteins may act as a signal for advanced glycosylation end product-mediated receptor uptake by macrophages and other cells and contribute to accelerated atherosclerosis in diabetes and uremia.


[DNA ploidy in epithelial ovarian cancer--an independent prognostic factor].
Ovarian cancer is the most lethal of the gynecological malignancies. One of the aims of the ongoing research in this field is the search for prognostic and/or predictive factors which can contribute to a more individualized patient treatment. All studies performed at The Norwegian Radium Hospital with regard to the prognostic significance of DNA ploidy in borderline, early and advanced ovarian cancer, were reviewed. The conclusions emanating from these studies were compared to the international literature. DNA ploidy analysis is of definite independent prognostic significance in borderline and early (FIGO stage I) ovarian cancer, and is of help in the selection of patients expected to benefit from adjuvant chemotherapy, or in whom a more conservative surgical procedure can be acceptable. DNA ploidy status is also of prognostic significance in advanced ovarian cancer; however, for the time being this information has no direct consequences for patient treatment. We conclude that DNA ploidy analysis should be incorporated in the routine histopathological evaluation of borderline and early (stage I) ovarian cancer.


Role of adenosine in hyperemic response of coronary blood flow in microembolization.
To investigate the pathophysiology of acute embolization of small coronary vessels and the role of adenosine in this abnormality, regional coronary blood flow (CBF), coronary vascular resistance, arteriovenous O2 difference, lactate extraction ratio, and adenosine release were studied in 39 anesthetized open-chest dogs after acute coronary embolization with microspheres of three different diameters (15 +/- 1, 94 +/- 8, and 293 +/- 23 microns). In 16 dogs, the left anterior descending coronary artery was embolized by repetitive injections of 15-microns microspheres, up to 4.4 +/- 0.4 X 10(5)/g myocardium; at this point CBF, determined by the electromagnetic flowmeter at the proximal site of the artery, was reduced toward zero. Up to 37% of total embolization, resting CBF increased to 175 +/- 36% of control; thereafter it decreased almost linearly as the extent of embolization was increased. After embolization, coronary arteriovenous O2 difference was significantly (P less than 0.01) decreased with a marked release of adenosine in the coronary vein. Despite a hyperemic flow response of CBF in the embolized area, myocardial ischemia was not prevented; maximal increase in CBF after 100-microns microsphere embolization (141 +/- 11% of control CBF, n = 6) was significantly (P less than 0.05) less than that in 15-micron microsphere embolization, whereas 300-microns microsphere embolization minimally increased CBF (123 +/- 13%, P greater than 0.1; n = 5). Hyperemic flow remained unchanged for at least 3 h when adenosine was persistently released. Theophylline significantly attenuated this response. These results indicate that in embolization with microspheres less than 300 microns in diameter, hyperemic response of coronary blood flow occurs, probably due to the hyperemia of nonoccluded vessels in the adjacent area of ischemic foci to adenosine released from the ischemic myocardium.


Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer: results from the WSG-AGO EC-Doc trial.
Taxane-anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 ≥ 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38-0.986), age <50 years old (HR = 1.682; 95 %CI 1.025-2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809-11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209-4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203-0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis.


Adaptive evolution of newly emerged micro-RNA genes in Drosophila.
How often micro-RNA (miRNA) genes emerged and how fast they evolved soon after their emergence are some of the central questions in the evolution of miRNAs. Because most known miRNA genes are ancient and highly conserved, these questions can be best answered by identifying newly emerged miRNA genes. Among the 78 miRNA genes in Drosophila reported before 2007, only 5 are confirmed to be newly emerged in the genus (although many more can be found in the newly reported data set; e.g., Ruby et al. 2007; Stark et al. 2007; Lu et al. 2008). These new miRNA genes have undergone numerous changes, even in the normally invariant mature sequences. Four of them (the miR-310/311/312/313 cluster, denoted miR-310s) were duplicated from other conserved miRNA genes. The fifth one (miR-303) appears to be a very young gene, originating de novo from a non-miRNA sequence recently. We sequenced these 5 miRNA genes and their neighboring regions from a worldwide collection of Drosophila melanogaster lines. The levels of divergence and polymorphism in these miRNA genes, vis-à-vis those of the neighboring DNA sequences, suggest that these 5 genes are evolving adaptively. Furthermore, the polymorphism pattern of miR-310s in D. melanogaster is indicative of hitchhiking under positive selection. Thus, a large number of adaptive changes over a long period of time may be essential for the evolution of newly emerged miRNA genes.


Persisting antibody reaction in paragonimiasis after praziquantel treatment is elicited mainly by egg antigens.
Antibody responses in serum and cerebrospinal fluid (CSF) samples from patients with active and chronic paragonimiasis and in sera from patients on whom follow-up studies were done after praziquantel treatment were analyzed using antigens of Paragonimus westermani prepared from eggs, metacercariae, juveniles of 4- and 7-week old, adult worms and recombinant protein of 28 kDa cruzipain-like cysteine protease (rPw28CCP). The patient sera/CSFs of active and chronic paragonimiasis revealed strong antibody reactions against the crude extracts of 4- and 7-week old juveniles as well as against those from egg and adult. rPw28CCP also showed specific reaction to the sera with active paragonimiasis. After the treatment, levels of specific antibodies in the sera gradually decreased to negative range in most patients. In some cases with persisting high antibody levels, however, the reactions at 27 kDa egg protein were sustained throughout the observation period of 34 months. The reactions at 35 and 32 kDa in adult extract and rPw28CCP disappeared rapidly after the treatment. Persistent antibody reactions even after successful treatment are provoked by continuous antigenic challenge from eggs which were not resolved by treatment.


Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia.
Frontline chemotherapy is successful against chronic lymphocytic leukemia (CLL), but results in untoward toxicity. Further, prognostic factors, cytogenetic anomalies, and compensatory cellular signaling lead to therapy resistance or disease relapse. Therefore, for the past few years, development of targeted therapies is on the rise. PI3K is a major player in the B-cell receptor (BCR) signaling axis, which is critical for the survival and maintenance of B cells. Duvelisib, a PI3K δ/γ dual isoform specific inhibitor that induces apoptosis and reduces cytokine and chemokine levels in vitro, holds promise for CLL. Areas covered: Herein, we review PI3K isoforms and their inhibitors in general, and duvelisib in particular; examine literature on preclinical investigations, pharmacokinetics and clinical studies of duvelisib either as single agent or in combination, for patients with CLL and other lymphoid malignancies. Expert opinion: Duvelisib targets the PI3K δ isoform, which is necessary for cell proliferation and survival, and γ isoform, which is critical for cytokine signaling and pro-inflammatory responses from the microenvironment. In phase I clinical trials, duvelisib as a single agent showed promise for CLL and other lymphoid malignancies. Phase II and III trials of duvelisib alone or in combination with other agents are ongoing.


SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Acute management of the endocrine complications of checkpoint inhibitor therapy.
Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3-4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1-2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed.


Influence of donor-acceptor distance variation on photoinduced electron and proton transfer in rhenium(I)-phenol dyads.
A homologous series of four molecules in which a phenol unit is linked covalently to a rhenium(I) tricarbonyl diimine photooxidant via a variable number of p-xylene spacers (n = 0-3) was synthesized and investigated. The species with a single p-xylene spacer was structurally characterized to get some benchmark distances. Photoexcitation of the metal complex in the shortest dyad (n = 0) triggers release of the phenolic proton to the acetonitrile/water solvent mixture; a H/D kinetic isotope effect (KIE) of 2.0 ± 0.4 is associated with this process. Thus, the shortest dyad basically acts like a photoacid. The next two longer dyads (n = 1, 2) exhibit intramolecular photoinduced phenol-to-rhenium electron transfer in the rate-determining excited-state deactivation step, and there is no significant KIE in this case. For the dyad with n = 1, transient absorption spectroscopy provided evidence for release of the phenolic proton to the solvent upon oxidation of the phenol by intramolecular photoinduced electron transfer. Subsequent thermal charge recombination is associated with a H/D KIE of 3.6 ± 0.4 and therefore is likely to involve proton motion in the rate-determining reaction step. Thus, some of the longer dyads (n = 1, 2) exhibit photoinduced proton-coupled electron transfer (PCET), albeit in a stepwise (electron transfer followed by proton transfer) rather than concerted manner. Our study demonstrates that electronically strongly coupled donor-acceptor systems may exhibit significantly different photoinduced PCET chemistry than electronically weakly coupled donor-bridge-acceptor molecules.


Lipids of dystrophic and normal mouse muscle: whole tissue and particulate fractions.
Myofibrillar, mitochondrial, and microsomal fractions were prepared from normal and dystrophic mouse limb muscle by differential centrifugation and analyzed for phospholipids and cholesterol. Fatty acids and aldehydes of neutral lipids and of phospholipids from whole muscle and particulate fractions were also determined. Normal microsomes contained more lecithin and less total ethanolamine phospholipids and cardiolipin than mitochondria. The myofibrils had an intermediate phospholipid composition, but their cholesterol-phospholipid ratio was smaller than that of the other two fractions. Except for an increased percentage of phosphatidalethanolamine in the dystrophic mitochondria, only the composition of the dystrophic microsomes differed from normal by containing less lecithin but more total ethanolamine phospholipid, phosphatidalethanolamine, sphingomyelin, and cholesterol. No significant differences were found in the fatty acid composition of neutral lipid extracts from normal and dystrophic preparations, but there was a significant decrease in the percentage of 22:6 in phospholipids from both dystrophic whole muscle and microsomes (-25% and -37%, respectively), whereas the 20:4 content was unaltered. By contrast, the percentages of 18:0 and total fatty aldehyde increased significantly. Phospholipid extracts from all dystrophic samples showed a significant decrease in 16:0 and an increase in 18:1 as compared with the normal.


Prediction of aggression on a locked psychiatric admissions ward.
The present study evaluates the accuracy of clinical and archival predictors of patients' aggressive behaviour on a locked admissions ward. Over a 9-month period, staff members estimated the likelihood that patients would become aggressive during their stay in the ward. These unaided clinical assessments were obtained with Visual Analogue Scales (VASs) administered before the end of the first full day of admission. Archival predictions were based on demographic variables (e.g. gender, number of previous admissions, diagnosis) derived from patients' admission forms. Aggressive behaviour was recorded with the Staff Observation Aggression Scale-Revised (SOAS-R). Clinical predictions of aggression were found to be moderately accurate. On the basis of clinical estimates, 75% of the patients were correctly classified as becoming aggressive or not. Although a body of evidence indicates that unaided clinical prediction of violent recidivism after hospital discharge does not perform well, it may be quite accurate in estimating short-term aggression risks during acute psychiatric admission.


End-of-life treatment of poly(vinyl chloride) and chlorinated polyethylene by dehydrochlorination in ionic liquids.
There is an urgent need for green technologies to remove halogens from halogenated polymers at the end of their lifetime. Ionic liquids (ILs) were used to dehydrochlorinate and/or dissolve the chlorinated polymers poly(vinyl chloride) (PVC) and chlorinated polyethylene (CPE). The dehydrochlorination activity of an IL depends mainly on its anion and is related to the high hydrogen-bond-accepting ability (β value) of the anion. Different phosphonium ILs successfully dissolve and dehydrochlorinate PVC and CPE at temperatures from 80 °C. PVC is dehydrochlorinated up to 98 % after 60 min in tetrabutylphosphonium chloride ([P4444 ][Cl]) at 180 °C. PVC pieces stabilized by calcium stearate (4 mm(3) ) are dehydrochlorinated more slowly; conversions of 85 and 96 % are reached after 1 and 8 h, respectively. Smaller pieces are dehydrochlorinated faster. High loadings, for example, 0.3 g stabilized PVC in 0.5 g IL, can be applied with only a minor loss of conversion. [P4444 ][Cl] proved to be stable during several consecutive reactions; after each run more than 99 % of the IL can be recovered. The structure of the dehydrochlorinated PVC was studied by (13) C cross-polarization magic-angle spinning NMR and FTIR spectroscopy; the removal of Cl and the formation of double bonds were confirmed. Carefully dehydrochlorinated CPE was processed further by acyclic diene metathesis depolymerization with ethylene and the Hoveyda-Grubbs second-generation catalyst to yield α,ω-dienes such as 1,5-hexadiene and 1,6-heptadiene.


Sodium transport effects on the basolateral membrane in toad urinary bladder.
In toad urinary bladder epithelium, inhibition of Na transport with amiloride causes a decrease in the apical (Vmc) and basolateral (Vcs) membrane potentials. In addition to increasing apical membrane resistance (Ra), amiloride also causes an increase in basolateral membrane resistance (Rb), with a time course such that Ra/Rb does not change for 1-2 min. At longer times after amiloride (3-4 min), Ra/Rb rises from its control values to its amiloride steady state values through a secondary decrease in Rb. Analysis of an equivalent electrical circuit of the epithelium shows that the depolarization of Vcs is due to a decrease in basolateral electromotive force (Vb). To see of the changes in Vcs and Rb are correlated with a decrease in Na transport, external current (Ie) was used to clamp Vmc to zero, and the effects of amiloride on the portion of Ie that takes the transcellular pathway were determined. In these studies, Vcs also depolarized, which suggests that the decrease in Vb was due to a decrease in the current output of a rheogenic Na pump. Thus, the basolateral membrane does not behave like an ohmic resistor. In contrast, when transport is inhibited during basolateral membrane voltage clamping, the apical membrane voltage changes are those predicted for a simple, passive (i.e., ohmic) element.


Pain as a predictor of frailty over time among older Mexican Americans.
The objective of this study was to examine pain as a predictor of frailty over 18 years of follow-up among older Mexican Americans who were nonfrail at baseline. Data were from a prospective cohort study of 1545 community-dwelling Mexican Americans aged ≥67 years from the Hispanic Established Populations for the Epidemiological Study of the Elderly (1995/1996-2012/2013). Frailty was defined as meeting 2 or more of the following: unintentional weight loss of >10 pounds, weakness, self-reported exhaustion, and slowness. The independent predictor was self-reported pain. Covariates included age, sex, marital status, education, comorbid conditions, body mass index, Mini-Mental State Examination, depressive symptoms, and limitation in activities of daily livings. General equation estimation was performed to estimate the odds ratio of frailty as a function of pain. A total of 538 participants (34.8%) reported pain at baseline. The prevalence of frailty among those with pain ranged from 24.4% in wave 3 to 41% in wave 8. The odds ratio of becoming frail over time as a function of pain was 1.71; 95% confidence interval: 1.41 to 2.09 after controlling for all covariates. Older age, hip fracture, high depressive symptoms, and activities of daily living disability were also associated with higher odds of becoming frail over time. Female participants and those with higher levels of education and high Mini-Mental State Examination scores were less at risk. In conclusion, pain was a significantly predictor of frailty. Early assessment and better management of pain may prevent early onset of frailty in older Mexican Americans.


P-selectin, L-selectin, and alpha 4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions.
The adhesive interactions of eosinophils with purified E-, P-, and L-selectins; vascular cell adhesion molecule-1 molecule; and HUVEC were examined in shear flow. Compared with neutrophils, eosinophils showed markedly less binding to E-selectin, but significantly stronger avidity for P-selectin. Both cell types showed a similar level of tethering and rolling on L-selectin. Eosinophils tethered and arrested abruptly on vascular cell adhesion molecule-1. However, some of the tethers were detached within several seconds; this was prevented by stimulation with eotaxin. Eosinophils also showed immediate arrest on HUVEC stimulated with 100 U/ml TNF-alpha for 6 h. Treatment with L-selectin mAb decreased eosinophil accumulation on the HUVEC by abrogating secondary tethers through interactions between flowing and attached eosinophils. mAb to P-selectin but not to E-selectin strongly inhibited primary tethers and accumulation of eosinophils. mAb to the integrin alpha 4 subunit inhibited arrest, induced rolling or detachment of tethered eosinophils, and resulted in partial reduction of eosinophil accumulation. mAb to the integrin beta 2 subunit had only a slight effect, whereas treatment with mAb to the integrin alpha 4 and beta 2 subunits together abolished rolling interactions as well as arrest, and thus almost totally inhibited eosinophil accumulation. Our data indicate that P-selectin, but not E-selectin, is directly involved in eosinophil tethering on inflammatory endothelium while L-selectin mainly mediates intereosinophil interaction. VLA-4 has a crucial role in eosinophil arrest, and arrest is enhanced by exposure to chemoattractants.


Different Predictors of Right and Left Ventricular Metabolism in Healthy Middle-Aged Men.
Dysfunction of the right ventricle (RV) plays a crucial role in the outcome of various cardiovascular diseases. Previous studies on RV metabolism are sparse although evidence implies it may differ from left ventricular (LV) metabolism. Therefore, the aims of this study were (1) to determine predictors of RV glucose uptake (GU) and free fatty acid uptake (FFAU) and (2) to compare them to predictors of LV metabolism in healthy middle-aged men. Altogether 28 healthy, sedentary, middle-aged (40-55 years) men were studied. Insulin-stimulated GU and fasting FFAU were measured by positron emission tomography and RV and LV structural and functional parameters by cardiac magnetic resonance. Several parameters related to whole-body health were also measured. Predictors of RV and LV metabolism were determined by pairwise correlation analysis, lasso regression models, and variable clustering using heatmap. RVGU was most strongly predicted by age and moderately by RV ejection fraction (EF). The strongest determinants of RVFFAU were exercise capacity (peak oxygen uptake), resting heart rate, LVEF, and whole-body insulin-stimulated glucose uptake rate. When considering LV metabolism, age and RVEF were associated also with LVGU. In addition, LVGU was strongly, and negatively, influenced by whole-body insulin-stimulated glucose uptake rate. LVFFAU was predicted only by LVEF. This study shows that while RV and LV metabolism have shared characteristics, they also have unique properties. Age of the subject should be taken into account when measuring myocardial glucose utilization. Ejection fraction is related to myocardial metabolism, and even so that RVEF may be more closely related to GU of both ventricles and LVEF to FFAU of both ventricles, a finding supporting the ventricular interdependence. However, only RV fatty acid utilization associates with exercise capacity so that better physical fitness in a relatively sedentary population is related with decreased RV fat metabolism. To conclude, this study highlights the need for further study designed specifically on less-known RV, as the results on LV metabolism and physiology may not be directly applicable to the RV.


Scaling up collaborative TB-HIV activities in Latin America.
TB-HIV collaborative activities are one of the cornerstones of TB control in the Stop TB strategy. Since 2003, most countries in Latin America and the Caribbean have been gradually implementing TB-HIV collaborative activities; however, limited information is currently available on the degree of implementation. This study is therefore aimed at describing to what degree TB-HIV collaborative activities are being implemented in 17 countries selected for the study. These countries were asked to complete a semi-structured questionnaire. An analysis of this questionnaire revealed that the challenges for TB-HIV collaboration lie in the fields of human resources, surveillance and HIV testing of TB patients.


Posterior Compartment Prolapse Occurrence After Anterior Vaginal Wall Suspension.
To determine the long-term rate of posterior compartment prolapse (PCP) occurrence after native tissue repair of the anterior compartment with anterior vaginal wall suspension (AVWS) procedure. An institutional review board approved surgical prolapse database was reviewed for women who underwent AVWS for any degree of anterior compartment prolapse with minimum of 6-month follow-up and no history of apical or posterior compartment repair. Demographic data, smoking status, parity, and uterine status were collected. The primary outcome was need for secondary PCP repair. A total of 300 women met inclusion criteria with a mean age of 63.8 ± 10.8 years, mean BMI of 26.1 ± 6.2 kg/m2, and a mean parity of 2.5 ± 1.4. At the time of AVWS 46 women (15%) had uterine-sparing AVWS, 74 (25%) had concomitant hysterectomy, and 180 (60%) had prior hysterectomy. Forty-eight women (16%) had secondary posterior compartment repair for PCP (60% abdominal route, 40% done vaginally) over a mean follow-up of 7.1 ± 4.4 years. At long-term follow-up, less than 20% of women undergoing AVWS underwent PCP repair.


[The prevalence of risk factors for coronary disease in workers of the Hospital General de México].
To evaluate the prevalence of risk factors of coronary heart disease in the personnel of the General Hospital in Mexico City. We studied 2,228 workers, 1,531 female (68.7%) and 697 male (31.2%) whose ages ranged from 16 to 65 years old in the period of 1993 to 1995. They were divided in work areas: Intendancy 477 (21.4%), Administrative, 697 (31.2%), Physicians, 495 (22.2%) and Nurses, 559 (25.0%). We collected clinical histories, anthropometric measures, and laboratory determinations of glucose, total cholesterol, LDL, HDL and triglicerydes. We found that 367 (14.9%) had total cholesterol above 240 mg/dl, with high values in females of the administrative area (17.1%) and males in the nursing department (26%), which was the highest tendency. Trigliceryde levels above 200 mg/dl were found in 208 males (24.6%) and 263 females (16.2%), with high prevalence in the nursing and administrative departments, in males (39.1 and 34.1% respectively). Obesity was present in 236 females (14.5%) and 97 males (11.5%). High blood pressure in 549 individuals (22.2%), 297 females (18.3%) and 252 males (29.8%) without significance regarding to work area. Smoking habits were positive in 32% of the total with highest prevalence in males from 30 to 45 years and in females from 30 to 50 years. We found an incidence of 6.24% of diabetes in all the subjects studied, 2.27% ignored the diagnosis at the moment they were studied. In this study we confirmed the high prevalence of risk factors of coronary heart disease in personnel of the General Hospital in Mexico City. In most cases, these risk factors that can be modified and, therefore, prevented.


Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial.
The aim of this study was to evaluate the efficacy and safety of mycophenolate sodium (MPS) in patients with primary Sjögren syndrome (pSS) refractory to other immunosuppressive agents. Eleven patients with pSS were treated with MPS up to 1,440 mg daily for an observation period of 6 months in this single-center, open-label pilot trial. At baseline, after 3 months, and after 6 months, we examined the clinical status, including glandular function tests, as well as different laboratory parameters associated with pSS. In addition, subjective parameters were determined on the basis of different questionnaires. Treatment with MPS was well tolerated in 8 of 11 patients. Due to vertigo or gastrointestinal discomfort, two patients did not complete the trial. One patient developed pneumonia 2 weeks after treatment and was withdrawn. In the remaining patients, MPS treatment resulted in subjective improvement of ocular dryness on a visual analogue scale and a reduced demand for artificial tear supplementations. However, no significant alterations of objective parameters for dryness of eyes and mouth were observed, although a substantial improvement of glandular functions occurred in two patients with short disease duration. In addition, treatment with MPS resulted in significant reduction of hypergammaglobulinemia and rheumatoid factors as well as an increase of complement levels and white blood cells. MPS promises to be an additional therapeutic option for patients with pSS, at least in those with shorter disease duration. Further investigations about the efficacy and safety of MPS in pSS have to be performed in larger numbers of patients.


Tests for two trees using likelihood methods.
This article considers two similar likelihood-based test statistics for comparing two fixed trees, the Kishino-Hasegawa (KH) test statistic and the likelihood ratio (LR) statistic, as well as a number of different methods for determining thresholds to declare a significant result. An explanation is given for why the KH test, which uses the KH test statistic and normal theory thresholds, need not give correct type I error probabilities under the appropriate null hypothesis. Simulations show that the KH test tends to give much smaller type I error probabilities than expected. The article presents a computationally efficient normal-theory parametric bootstrap method for determining better KH test statistic thresholds. For the LR statistic, existing mixture of chi-squares results for determining thresholds are extended to cases in which a tree with two or three zero edge-lengths exhibits the two trees being compared. The resulting chi-bar test and use of the KH test statistic with normal bootstrap are shown through simulation to give good performance but are more difficult to implement than the KH test. Two conservative approaches are presented which require only log likelihoods and simple chi-square thresholds. While they did not perform as well as chi-bar and normal bootstrap methods in the simulations considered, they gave better performance than the KH test and have just as simple an implementation. As a by-product of parametric bootstrap considerations, an adjustment to the Swofford-Olsen-Waddell-Hillis (SOWH) test is proposed.


Studies on the reaction of trans-2-heptenal with peanut proteins.
Hexanal, 2-heptenal, and nonanal were identified as relevant reaction products formed in the course of the lipid peroxidation of heated peanut oil. For the identification of potential amino acid side chain adducts, kinetic studies between N(α)-benzoylglycyl-l-lysine as a model for protein-bound lysine and trans-2-heptenal were performed, showing a strong decrease of the lysine-derivative whereupon the loss of trans-2-heptenal was moderate. Following acid hydrolysis of the incubation mixture of N(α)-acetyl-l-lysine and trans-2-heptenal, two UV-active major lipation products were observed, isolated and identified as isomeric pyridinium-derivatives, namely (Z)- and (E)-1-(5-amino-5-carboxypentyl)-4-butyl-3-(pent-1-en-1-yl)pyridin-1-ium (cis- and trans-BPP-lysine). After heating of a native peanut protein extract with trans-2-heptenal, both derivatives were quantitated by LC-ESI-MS/MS after acid hydrolysis and the modification of lysine was measured by amino acid analysis. At low, "food-relevant", concentrations of trans-2-heptenal, up to 80% of the lysine modification could be explained by the formation of cis- and trans-BPP-lysine, showing that these two lipation derivatives represent good markers for a protein modification by the lipid peroxidation product trans-2-heptenal.


External validation on a prospective basis of a nomogram for predicting the time to first treatment in patients with chronic lymphocytic leukemia.
A nomogram that incorporates traditional and newer prognostic factors to identify patients with chronic lymphocytic leukemia (CLL) who are at high risk of receiving therapy was developed by investigators at The University of Texas M. D. Anderson Cancer Center (MDACC). Because the model required validation before its extensive use could be recommended, the authors sought to externally validate the nomogram in an independent, community-based cohort of patients with CLL. In total, 328 previously untreated patients with newly diagnosed, asymptomatic, Binet stage A CLL from different primary hematology centers who were registered on a prospective basis during 2006 to 2010 on an observational database of the Italian Lymphoma Study Group were considered suitable for external validation of the model. A total point score was calculated for each patient using a formula proposed by MDACC investigators, and the median score was 19.9 (range, 0-69.5). Furthermore, when the score was evaluated as continuous variable (ie, by measuring the risk of each point increase), the total point score was associated with the time to first treatment (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.02-1.05; P < .0001). Receiver operating characteristic analysis identified a point score of 25 (area under curve; 0.64; sensitivity, 61.5; specificity, 72.1; P < .0001) as the best threshold capable of separating patients who needed therapy from patients who did not (HR, 3.27; 95% CI, 2,07-5.18; P < .0001). The prognostic index category also remained a predictor of the time to first treatment when the analysis was limited to patients with Rai stage 0 disease (HR, 4.05; 95% CI, 2.25-7.52; P < .0001). Finally, a goodness-of-fit test demonstrated that the nomogram model had a significantly good fit at 2 years (correlation coefficient [r(2) ] = 0.966; P = .002). The current results confirmed the ability of a newly developed prognostic index to predict the time to first treatment among previously untreated patients with CLL who had early disease and extended the utility of the model to those with Rai stage 0 disease. In addition, the actual and predicted time to first treatment outcomes revealed good agreement, suggesting that, externally, the results provided by the model are well calibrated. Cancer 2013. © 2012 American Cancer Society.


Developing a conceptual model of possible benefits of condensed tannins for ruminant production.
Enteric methane (CH4) emissions from ruminants have compelled a wide range of research initiatives to identify environmental abatement opportunities. However, although such mitigations can theoretically be attained with feed additives and feeding strategies, the limited empirical evidence on plant extracts used as feed additives does not support extensive or long-term reductions. Nevertheless, their strategic use (i.e. alone or combined in a simultaneous or consecutive use) may provide not only acceptable CH4 abatement levels, but also relevant effects on animal physiology and productivity. Condensed tannins (CT) represent a range of polyphenolic compounds of flavan-3-ol units present in some forage species that can also be added to prepared diets. Methods to determine CT, or their conjugated metabolites, are not simple. Although there are limitations and uncertainties about the methods to be applied, CT are thought to reduce CH4 production (1) indirectly by binding to the dietary fibre and/or reducing the rumen digestion and digestibility of the fibre and (2) directly by inhibiting the growth of rumen methanogens. On the basis of their role in livestock nutrition, CT influence the digestion of protein in the rumen because of their affinity for proteins (e.g. oxidative coupling and H bonding at neutral pH) that causes the CT-protein complex to be insoluble in the rumen; and dissociate in the abomasum at pH 2.5 to 3.0 for proteolysis and absorption in the small intestine. CT may also reduce gastro-intestinal parasite burdens and improve reproductive performance, foetal development, immune system response, hormone serum concentrations, wool production and lactation. The objectives of this paper are to discuss some of the beneficial and detrimental effects of CT on ruminant production systems and to develop a conceptual model to illustrate these metabolic relationships in terms of systemic physiology using earlier investigations with the CT-containing legume Lotus corniculatus. Our conceptual model indicated four complex and long-lasting relationships (digestive, toxicological, physiological and morphological) that can alter the normal biology of the animal. These relationships are interdependent, integrative, and sometimes, complementary to each other. This conceptual model can be used to develop mechanistic models to improve the understanding of the interaction between CT and the ruminants as well as to guide research initiatives of the impact of polyphenol-rich foods on human health.


Detection of Cutaneous Leishmaniasis Foci in South Ethiopia.
Cutaneous leishmaniasis (CL) is a major public health problem in Ethiopia. The disease is endemic in Ochollo, a village in southern Ethiopia, but there are no reports of CL in the wider area, although it is ecologically very similar. We conducted a rapid assessment survey in the South Ethiopian Rift Valley and found 100 parasitologically confirmed CL cases in 38 villages not reported endemic for CL. Approximately half of the cases were children (57%), and most lesions occurred on the face (78%) and were older than 6 months (77%). Only 2% of the people was aware of the mode of transmission, and 9% sought modern treatment at a hospital. These preliminary data indicate that CL is much more widespread than previously reported and that the disease might have a large psychosocial impact. Hence, this study calls for larger surveys across the Ethiopian highlands. Additionally, health education and treatment capacity need to be implemented.


[Rethoracotomy in thoracic surgery].
Technical progress of recent years allowed thoracic surgery to become a safer procedure. Experience of thoracic operations in our institution counts up to 14 962 cases (1963-2009 yy). Of them 223 (1.5%) patients had rethoracotomies on the reason of various operative complications. 112 patients had the intrapleural bleeding, 56 patients were reoperated on the reason of coagulated hemothorax, 57 patients demonstrated the bronchial stump insufficiency, and 11 were reoperated on other reasons. The frequency of rethoracotomy had decreased from 2.5 to 0.2%. The on-time rethoracotomy allows to save the patients' life and do not aggravate the overall result of the treatment.


Identification and Characterization of Arbutus unedo L. Endophytic Bacteria Isolated from Wild and Cultivated Trees for the Biological Control of Phytophthora cinnamomi.
Arbutus unedo L. is a resilient tree with a circum-Mediterranean distribution. Besides its ecological relevance, it is vital for local economies as a fruit tree. Several microorganisms are responsible for strawberry tree diseases, leading to production constrictions. Thus, the development of alternative plant protection strategies is necessary, such as bacterial endophytes, which may increase their host's overall fitness and productivity. As agricultural practices are a driving factor of microbiota, this paper aimed to isolate, identify and characterize endophytic bacteria from strawberry tree leaves from plants growing spontaneously in a natural environment as well as from plants growing in orchards. A total of 62 endophytes were isolated from leaves and identified as Bacillus, Paenibacillus, Pseudomonas, Sphingomonas and Staphylococcus. Although a slightly higher number of species was found in wild plants, no differences in terms of diversity indexes were found. Sixteen isolates were tested in vitro for their antagonistic effect against A. unedo mycopathogens. B. cereus was the most effective antagonist causing a growth reduction of 20% in Glomerella cingulata and 40% in Phytophthora cinnamomi and Mycosphaerella aurantia. Several endophytic isolates also exhibited plant growth-promoting potential. This study provides insights into the diversity of endophytic bacteria in A. unedo leaves and their potential role as growth promoters and pathogen antagonists.


Absorption of all-trans and 9-cis beta-carotene in human ileostomy volunteers.
1. Mass balance studies were carried out in fasted ileostomy subjects (n = 5) given an oral physiological dose (10 mg) of beta-carotene [all-trans: 9-cis, 84:16 (w/w)] dispersed in vegetable oil. Blood and ileal effluent samples were collected and analysed for beta-carotene. 2. Results showed that 90% (range 97.0-74.3%) of the total beta-carotene was absorbed without measurable perturbation of plasma total beta-carotene concentration, or change in the all-trans: 9-cis beta-carotene ratio. Peak loss of beta-carotene in ileal effluent occurred at 4.9 h (range 2.9-8.4 h) postingestion, and no further loss was detected after 5.4-12.4 h, depending upon the individual. Comparison of the ratio of all trans-beta-carotene to 9 cis-beta-carotene in the test meal and effluent indicated that isomerization did not occur during passage through the gastrointestinal tract and that both isomers were similarly absorbed. However, the all-trans: 9-cis beta-carotene ratio of the plasma did not change. Reasoned assumptions allowed the construction of a mathematical model of plasma beta-carotene disposal. 3. It is concluded that physiological doses of isolated all-trans and 9-cis beta-carotene are well absorbed without necessarily causing detectable excursions in plasma beta-carotene concentrations, or altering the ratio of all-trans to 9-cis beta-carotene. Isomerization of beta-carotene does not occur during passage through the gastrointestinal tract. Absorbed beta-carotene is rapidly cleared from the plasma to an unobservable pool at a rate similar to that of chylomicron triacylglycerol.


Photobiomodulation (blue and green light) encourages osteoblastic-differentiation of human adipose-derived stem cells: role of intracellular calcium and light-gated ion channels.
Human adipose-derived stem cells (hASCs) have the potential to differentiate into several different cell types including osteoblasts. Photobiomodulation (PBM) or low level laser therapy (LLLT) using red or near-infrared wavelengths has been reported to have effects on both proliferation and osteogenic differentiation of stem cells. We examined the effects of delivering four different wavelengths (420 nm, 540 nm, 660 nm, 810 nm) at the same dose (3 J/cm(2)) five times (every two days) on hASCs cultured in osteogenic medium over three weeks. We measured expression of the following transcription factors by RUNX2, osterix, and the osteoblast protein, osteocalcin. The 420 nm and 540 nm wavelengths were more effective in stimulating osteoblast differentiation compared to 660 nm and 810 nm. Intracellular calcium was higher after 420 nm and 540 nm, and could be inhibited by capsazepine and SKF96365, which also inhibited osteogenic differentiation. We hypothesize that activation of light-gated calcium ion channels by blue and green light could explain our results.


Minimally invasive endoscopic management of subglottic stenosis in children: success and failure.
To assess the efficacy and safety of endoscopic management of subglottic stenosis both as a primary and as an adjunctive treatment in the pediatric population. Retrospective review of pediatric patients with subglottic stenosis undergoing endoscopic airway procedures at a tertiary care pediatric medical center. Outcomes were assessed by systematic review to determine the success and failure of the endoscopic approach. Forty patients (22 male, 18 female) underwent endoscopic interventions for a diagnosis of subglottic airway stenosis between 2003 and 2006. Age ranged from 22 days old to 20 years old. Recorded degree of subglottic stenosis ranged from 10% to 99%. Fifty-three percent (21/40) had a history of prematurity, and 40% (16/40) had secondary airway diagnoses. Twenty-four patients underwent an endoscopic intervention initially (including laser or dilation, with or without topical mitomycin treatment), including four patients who underwent tracheostomy prior to the first endoscopic intervention. Sixteen underwent laryngotracheoplasty initially, including ten patients who underwent tracheostomy prior to the laryngotracheoplasty. Endoscopic treatment resulted in resolution of symptoms, and/or decannulation, and no further need for an open procedure in 58% of patients. Of the 24 patients undergoing endoscopic interventions initially, 14 patients underwent two or more endoscopic interventions, and 10 patients subsequently required tracheostomy or laryngotracheoplasty. When endoscopic procedures were used as an adjunct to laryngotracheoplasty, 60% (12/20) had resolution of symptoms, underwent decannulation, and did not require tracheostomy or revision laryngotracheoplasty. The endoscopic approach can be successful in the management of properly selected patients with subglottic stenosis, either as the initial treatment modality or as an adjunctive treatment in cases of re-stenosis after open airway surgery. The likelihood of success with a minimally invasive procedure as the primary treatment decreases with worsening initial grade of subglottic stenosis.


"Hard-earned wisdom: Exploratory processing of difficult life experience is positively associated with wisdom": Correction to Weststrate and Glück (2017).
Reports an error in "Hard-earned wisdom: Exploratory processing of difficult life experience is positively associated with wisdom" by Nic M. Weststrate and Judith Glück (Developmental Psychology, 2017[Apr], Vol 53[4], 800-814). The affiliation of Nic M. Weststrate was inadvertently set as "Relationships and Life Experiences" in the article byline. It should have been "University of Toronto". The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-12497-007.) Laypersons and experts believe that wisdom is cultivated through a diverse range of positive and negative life experiences. Yet, not all individuals with life experience are wise. We propose that one possible determinant of growth in wisdom from life experience is self-reflection. In a life span sample of adults (N = 94) ranging from 26 to 92 years of age, we examined wisdom's relationship to self-reflection by investigating "why" people report reflecting on the past (i.e., reminiscence functions) and "how" they reflect within autobiographical memories of difficult life events (i.e., autobiographical reasoning). We assessed wisdom using self-report, performance, and nomination approaches. Results indicated that wisdom was unrelated to the frequency of self-reflection; however, wiser people differed from others in their (a) reasons for reminiscence and (b) mode of autobiographical reasoning. Across 3 methods for assessing wisdom, wisdom was positively associated with exploratory processing of difficult life experience (meaning-making, personal growth), whereas redemptive processing (positive emotional reframing, event resolution) was positively associated with adjustment. This study suggests that developmental pathways in the wake of adversity may be partially determined by how individuals self-reflectively process significant life experiences. (PsycINFO Database Record


Cell guidance by ultrafine topography in vitro.
Laser holography and microelectronic fabrication techniques have been employed to make grating surfaces in fused quartz with ultrafine period (260 nm) in an attempt to mimic the topography of aligned fibrillar extracellular matrix (ECM), which, in the past, has been shown to affect the behaviour of cells in vitro and in vivo. The alignment of BHK cells, MDCK cells and chick embryo cerebral neurones on 260 nm period grating surfaces (130 nm grooves separated by 130 nm) of various depths (100, 210 and 400 nm) was examined. While all gratings aligned BHK cell populations, the degree of alignment was dependent on depth. The response of single MDCK cells to the grating patterns was both to align precisely to the direction of the gratings, and to elongate; only their elongation was depth-dependent. MDCK cells that were part of epithelial cell islands, and the outgrowth of neurites from chick embryo neurones, were mainly unaffected by the grating surfaces. It is clear that topography on this scale can control cell behaviour, but guidance of this type is strongly dependent on cell type and cell-cell interactions.


Circ_0005875 sponges miR-502-5p to promote renal cell carcinoma progression through upregulating E26 transformation specific-1.
Increasing evidence has shown that circular RNAs (circRNAs) play critical roles in various cancers, including renal cell carcinoma (RCC). We aimed to explore the role and underlying mechanism of circ_0005875 in RCC. The expression levels of circ_0005875, microRNA-502-5p (miR-502-5p) and E26 transformation specific-1 (ETS1) mRNA were determined by quantitative real-time PCR. Cell proliferation was assessed by Cell Counting Kit-8, colony formation, and 5-Ethynyl-2'-deoxyuridine (EdU) assays. Cell migration and invasion were monitored by wound healing assay and transwell assay, respectively. Flow cytometry analysis was applied to determine cell apoptosis and cell cycle distribution. Western blot assay was performed to measure the protein expression of CyclinD1 and ETS1. The interaction between miR-502-5p and circ_0005875 or ETS1 was confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. A xenograft tumor model was established to confirm the role of circ_0005875 in vivo. Circ_0005875 and ETS1 were upregulated and miR-502-5p was downregulated in RCC tissues and cells. Knockdown of circ_0005875 suppressed RCC cell proliferation, migration and invasion, and induced apoptosis and cell cycle arrest. MiR-502-5p was a target of circ_0005875, and miR-502-5p inhibition reversed the inhibitory effects of circ_0005875 knockdown on the malignant behaviors of RCC cells. ETS1 was a direct target of miR-502-5p, and miR-502-5p exerted its anti-tumor role in RCC cells by targeting ETS1. Moreover, circ_0005875 knockdown decreased ETS1 expression by sponging miR-502-5p. Additionally, circ_0005875 depletion suppressed tumor growth in vivo. Circ_0005875 knockdown suppressed RCC progression by regulating miR-502-5p/ETS1 axis, which might provide a promising therapeutic target for RCC.


Structural determination of archaeal UDP-N-acetylglucosamine 4-epimerase from Methanobrevibacter ruminantium M1 in complex with the bacterial cell wall intermediate UDP-N-acetylmuramic acid.
The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4-epimerase; WbpP; EC 18.104.22.168), from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 Å. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann-fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short-chain dehydrogenases/reductases superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases. The protein was co-crystallized with coenzyme NADH and UDP-N-acetylmuramic acid, the latter an unintended inclusion and well known product of the bacterial enzyme MurB and a critical intermediate for bacterial cell wall synthesis. This is a non-native UDP sugar amongst archaea and was most likely incorporated from the E. coli expression host during purification of the recombinant enzyme.


A Controlled Study to Examine the Effect of Topical Sucralfate on Radiofrequency-induced Burn Wounds in Rats
Several preclinical studies have shown topical sucralfate facilitates wound repair. This study aimed to evaluate the effect of 10% topical sucralfate on healing radiofrequency-induced burn wounds in rats. Twenty (20) male rats were divided into 2 equal groups. Using radiofrequency, 4 full-thickness, 1 cm in diameter round burns were created on the backs of the rats that then were randomized to receive twice-daily treatment for 30 days with 10% sucralfate or neutral cream. Biopsies were taken on days 4, 7, 14, and 21 to analyze fibrin-leukocyte crut, edema density, epidermal-dermal cell infiltration, amount of fibroblast and collagen fibers, amount of elastic fibers, neovascularization-angiogenesis, and reepithelialization-granulation tissue. Data were collected to a spreadsheet and entered into statistical software for analysis. Histopathological features were classified as categorical variables and compared using the χ2 test and Fisher's exact test. When χ2 was used, Yates' correction for continuity was performed. All reported P values were 2-tailed; P less than .05 was considered statistically significant. On day 4, improvement in edema density (P = .034), epidermal detachment (P = .020), epidermal-dermal cell infiltration (P = .007), and polymorphonuclear leukocyte infiltration (P = .021) were statistically more significant in the sucralfate than control group. On day 7, epidermal-dermal cell infiltration (P = .007) and elastic fibers P = .050) were statistically more significant in the sucralfate group. On day 14, angiogenesis (P = .029), reepithelialization (P = .035), and granulation tissue (P = .003) were statistically more significant in the sucralfate group. By the end of the study (day 30), angiogenesis (P = .010), reepithelialization (P <.001), fibroblast density (P = .016), granulation tissue (P = .035), and collagen density (P = .002) were significantly improved in the sucralfate group versus the control group. In a rat wound model, 10% topical sucralfate was found to histopathologically facilitate the healing process compared to the control group. Controlled clinical studies are needed to elucidate the effect of this treatment in human wounds.


Asthma and vitamin D in Brazilian adolescents: Study of Cardiovascular Risks in Adolescents (ERICA).
To evaluate the association between asthma prevalence and serum levels of vitamin D in Brazilian adolescents. This was a cross-sectional, school-based study involving adolescents between 12-17 years of age from four large Brazilian cities located at different latitudes (Fortaleza, Rio de Janeiro, Brasília, and Porto Alegre). Information on asthma diagnosis, lifestyle, and sociodemographic characteristics was collected by means of self-administered questionnaires. Serum concentrations of calcifediol were dichotomized as sufficient (≥ 20 ng/mL) or insufficient/deficient (< 20 ng/mL) levels. Bivariate analyses were carried out between vitamin D levels and prevalence of active asthma (AA), as well as other variables in study, using the chi-square test. Generalized linear models were configured to analyze potential confounding factors (p < 0.20). Between 2013 and 2014, 1,053 adolescents were evaluated. The prevalences of AA and insufficient/deficient levels of calcifediol were 15.4% and 21%, respectively. There were no statistically significant associations between AA and hypovitaminosis D. The prevalences of AA and vitamin D insufficiency were, respectively, 2.34 (95% CI, 1,28-4.30) and 3.22 (95% CI, 1.75-5.95) times higher in Porto Alegre than in Rio de Janeiro, regardless of possible confounding factors. However, no significant associations were found between the prevalence of AA and vitamin-D-related variables in any of the cities. No association was found between AA and low levels of vitamin D in adolescents living at different latitudes in Brazil.


Small-molecule mimicry hunting strategy in the imperial cone snail, Conus imperialis.
Venomous animals hunt using bioactive peptides, but relatively little is known about venom small molecules and the resulting complex hunting behaviors. Here, we explored the specialized metabolites from the venom of the worm-hunting cone snail, Conus imperialis Using the model polychaete worm Platynereis dumerilii, we demonstrate that C. imperialis venom contains small molecules that mimic natural polychaete mating pheromones, evoking the mating phenotype in worms. The specialized metabolites from different cone snails are species-specific and structurally diverse, suggesting that the cones may adopt many different prey-hunting strategies enabled by small molecules. Predators sometimes attract prey using the prey's own pheromones, in a strategy known as aggressive mimicry. Instead, C. imperialis uses metabolically stable mimics of those pheromones, indicating that, in biological mimicry, even the molecules themselves may be disguised, providing a twist on fake news in chemical ecology.


Analyzing Structure-Activity Variations for Mn-Carbonyl Complexes in the Reduction of CO2 to CO.
Contemporary electrocatalysts for the reduction of CO2 often suffer from low stability, activity, and selectivity, or a combination thereof. Mn-carbonyl complexes represent a promising class of molecular electrocatalysts for the reduction of CO2 to CO as they are able to promote this reaction at relatively mild overpotentials, whereby rare-earth metals are not required. The electronic and geometric structure of the reaction center of these molecular electrocatalysts is precisely known and can be tuned via ligand modifications. However, ligand characteristics that are required to achieve high catalytic turnover at minimal overpotential remain unclear. We consider 55 Mn-carbonyl complexes, which have previously been synthesized and characterized experimentally. Four intermediates were identified that are common across all catalytic mechanisms proposed for Mn-carbonyl complexes, and their structures were used to calculate descriptors for each of the 55 Mn-carbonyl complexes. These electronic-structure-based descriptors encompass the binding energies, the highest occupied and lowest unoccupied molecular orbitals, and partial charges. Trends in turnover frequency and overpotential with these descriptors were analyzed to afford meaningful physical insights into what ligand characteristics lead to good catalytic performance, and how this is affected by the reaction conditions. These insights can be expected to significantly contribute to the rational design of more active Mn-carbonyl electrocatalysts.


Zidovudine therapy and HIV type 1 mutations in children with symptomatic HIV type 1 infection: effect of switching to didanosine or zidovudine plus didanosine therapy. Italian Multicenter Study Group on HIV Mutations in Children.
Type and prevalence of zidovudine (ZDV) resistance mutations in HIV-1-infected children in clinically stable condition and on ZDV monotherapy were analyzed to evaluate the effect of switching to didanosine (ddI) monotherapy or to ZDV plus ddI on the pattern of mutations and on the clinical outcome. Monthly clinical and laboratory controls for HIV-1 infection status were performed; at enrollment and every 4 to 6 months after treatment randomization mutant proviral sequences were evaluated in all the children, whereas viral burden was performed only in a small subgroup of patients randomly selected in each of the three treatment groups. ZDV resistance-associated proviral DNA mutations were defined as low-level resistance (LLR) mutations or medium/high-level resistance (MHLR) mutations; clinical outcome was considered as stable or deteriorating. Results showed that at entry into the study the duration of ZDV therapy was significantly correlated with the presence of mutations, and that the level of resistance given by mutations was associated with the severity both of symptoms and immunodeficiency. After randomization to treatment, in patients with mutations that confer LLR a better clinical outcome with ddI monotherapy than with ZDV plus ddI and ZDV alone was observed in the subsequent 6 months, whereas in patients with mutations that confer MHLR no significant difference among the three treatment groups was found. Data showed also that levels of viral burden at the time of changing therapy are related to clinical outcome if measured by plasma viral load. These results suggest that genotypic resistance assays, together with viral load, may prove useful for rational treatment decisions both at the start of therapy and with failure.


Leucine-Rich Alpha-2-Glycoprotein 1 in Serum Is a Possible Biomarker to Predict Response to Preoperative Chemoradiotherapy for Esophageal Cancer.
The purpose of the present study was to identify a biomarker that can predict the response to preoperative chemoradiotherapy (PCRT) in esophageal cancer patients. Twenty-five serum samples collected from patents with esophageal cancer before PCRT (responder = 13, non-responder = 12) were analyzed by quantitative proteomics, and 248 proteins were identified. Among them, the serum levels of leucine-rich alpha-2-glycoprotein 1 (LRG1) were significantly different (p < 0.01) and well discriminated (area under the curve (AUC) of the receiver operating characteristic (ROC) curve >0.8) between responder and non-responder groups. The combination of LRG1 with C-reactive protein (CRP) and soluble interleukin-6 receptor (sIL-6R), which were previously reported as biomarkers predicting PCRT response, further improved the predictive performance, providing an AUC of greater than 0.9. The present results suggest that LRG1 and its combination with CRP and sIL-6R are promising biomarker candidates to predict response to PCRT in esophageal cancer patients.


The lethality of penetrating cardiac wounds.
The objective was to review our experience in the presentation and management of patients with penetrating cardiac injuries, using physiologic and anatomic indices. The setting was a 400-bed Level I urban trauma center. A 6-year retrospective case study was undertaken. The revised trauma score, physiologic index (PI), penetrating cardiac trauma index, penetrating thoracic trauma index, penetrating trauma index, and cardiac injury organ score were determined. Fifty patients responded to emergency room resuscitation and reached the operating room. Overall survival was 66 per cent. The admission PI correlated well with outcome. Patients presenting in shock (PI, 10; revised trauma score, 7-10) appeared to have higher survival rates when compared to those patients with a normotensive presentation. Twenty-three per cent of patients admitted with a PI < or = 10 died despite reaching the operating room within a mean of 45 minutes. Although the majority of patients who reach the operating room survive, a significant number of (initially normotensive) patients die soon after cardiorrhaphy.


Proteoglycans on normal and migrating human corneal endothelium.
Proteoglycans are of fundamental importance to the normal functioning of the cornea. They consist of a core protein to which one or more glycosaminoglycan chains are attached. Cell surface proteoglycans are known to mediate many aspects of cell behaviour including cell adhesion, control of extracellular matrix deposition, cell proliferation, cell migration, leukocyte adhesion and modulation of growth factor activity. This paper describes the first investigation into the distribution and function of the three main classes of proteoglycans on human corneal endothelium. Immuno-gold labelling techniques were used at the light, scanning and transmission electron microscope level to localise heparan sulphate, chondroitin sulphate and keratan sulphate proteoglycans on human corneal endothelium. Human corneas were freeze-wounded and kept in organ culture for 3 days in order to study the distribution of proteoglycans on migrating corneal endothelium. An Optimas image analysis system was used to quantify the change in proteoglycan labelling during cell migration. Labelling for chondroitin sulphate and heparan sulphate was at very low levels on normal corneal endothelium while keratan sulphate labelling was at high levels. The wound healing experiments showed that migrating cells had increased labelling for heparan sulphate and chondroitin sulphate with greatly decreased labelling for keratan sulphate. Statistical analysis showed these changes were highly significant (P<0.001). Transmission electron microscopy revealed that chondroitin sulphate and keratan sulphate were present throughout Descemet's membrane while heparan sulphate was concentrated at the interface of Descemet's membrane and the migrating corneal endothelial cells. The pattern of occurrence of chondroitin sulphate, heparan sulphate and keratan sulphate on the human endothelium in normal and wounded cornea suggests that these proteoglycans are linked to the process of cell migration.


Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor.
SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1 is a primary transcriptional coregulator for estrogen receptor (ER). Six SRC-3 phosphorylation sites have been identified, and these can be induced by steroids, cytokines, and growth factors, involving multiple kinase signaling pathways. Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor alpha (ERalpha) or activated ERbeta is present. Both the activation function 1 and the ligand binding domains of ERalpha are required for maximal induction. Mutations in the coactivator binding groove of the ERalpha ligand binding domain inhibit E2-stimulated SRC-3 phosphorylation, as do mutations in the nuclear receptor-interacting domain of SRC-3, suggesting that ERalpha must directly contact SRC-3 for this posttranslational modification to take place. A transcriptionally inactive ERalpha mutant which localizes to the cytoplasm supports E2-induced SRC-3 phosphorylation. Mutations of the ERalpha DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation. Together these data demonstrate that E2-induced SRC-3 phosphorylation is dependent on a direct interaction between SRC-3 and ERalpha and can occur outside of the nucleus. Our results provide evidence for an early nongenomic action of ER on SRC-3 that supports the well-established downstream genomic roles of estrogen and coactivators.


[Some indices of lipids metabolism and antioxidant profile in geriatric patients with arterial hypertension].
Arterial hypertension contributes essentially into development of chronic heart failure and chronic ischemia of the brain, which results in social dependence of geriatric patients. One of the important factors in the development of arterial hypertension is the state of lipids peroxidation. Misbalance among the products of lipids peroxidation and components of antioxidation defense system revealed in cardiovascular diseases (mainly in arterial hypertension and heart failure) promotes progress of these diseases and premature aging of an organism. The therapy aimed at normalization of the oxidative profile of the patients with arterial hypertension should include prolonged beta-blockers, ACE inhibitors, calcium antagonists, statines and polyvitamin complexes with vitamins A and E.


Localized electronic structures of graphene oxide studied using scanning tunneling microscopy and spectroscopy.
We have used scanning tunneling microscopy (STM) to elucidate the nanoscale electronic structures of graphene oxide (GO). The unreduced GO layer was imaged using STM without reduction processes when deposited on a Au(111) surface covered with an octanethiolate self-assembled monolayer (C8S-SAM). The STM image of the GO sheet exhibits a grainy structure having a thickness of about 1 nm, which is in good agreement with the previous results obtained using atomic force microscopy (AFM). We found that the C8S-SAM suppresses the adsorption of water remaining on the substrate, which would be important to accomplish the nanoscale imaging of the unreduced GO by STM. Furthermore, we successfully detected the π and π* states localized in the GO sheet using scanning tunneling spectroscopy (STS). The π-π* gap energy and the gap center are not uniform within the GO sheet, indicating the existence of various sizes of the sp2 domain and evidence for the local electronic doping by the substituents.


Genome-wide association study of type 2 diabetes in Africa.
Genome-wide association studies (GWAS) for type 2 diabetes have uncovered >400 risk loci, primarily in populations of European and Asian ancestry. Here, we aimed to discover additional type 2 diabetes risk loci (including African-specific variants) and fine-map association signals by performing genetic analysis in African populations. We conducted two type 2 diabetes genome-wide association studies in 4347 Africans from South Africa, Nigeria, Ghana and Kenya and meta-analysed both studies together. Likely causal variants were identified using fine-mapping approaches. The most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10-13). Fine-mapping of the TCF7L2 locus suggested one type 2 diabetes association signal shared between Europeans and Africans (indexed by rs7903146) and a distinct African-specific signal (indexed by rs17746147). We also detected one novel signal, rs73284431, near AGMO (p = 5.2 × 10-9, minor allele frequency [MAF] = 0.095; monomorphic in most non-African populations), distinct from previously reported signals in the region. In analyses focused on 100 published type 2 diabetes risk loci, we identified 21 with shared causal variants in African and non-African populations. These results demonstrate the value of performing GWAS in Africans, provide a resource to larger consortia for further discovery and fine-mapping and indicate that additional large-scale efforts in Africa are warranted to gain further insight in to the genetic architecture of type 2 diabetes.


Molecular cloning and cell cycle-dependent expression of mammalian CRM1, a protein involved in nuclear export of proteins.
Crm1 of Schizosaccharomyces pombe, a nuclear protein essential for proliferation and chromosome region maintenance, is a possible target of leptomycin B, an antifungal and antitumor antibiotic with cell cycle-arresting activity. cDNA encoding a human homolog of Crm1 was cloned. Human CRM1 (hCRM1) consisted of 1071 amino acids, of which the sequence showed 52% homology with S. pombe Crm1. hCRM1 weakly complemented the cold-sensitive mutation of S. pombe crm1-809, as did S. pombe crm1+. Overproduction of hCRM1 under the control of a series of nmt1 promoters suppressed cell proliferation in wild-type S. pombe in an expression level-dependent manner. A similar inhibitory effect was also observed for crm1+. Cells overproducing either hCRM1 or S. pombe Crm1 were distinctly larger than uninduced cells and contained compacted and fragmented nuclei. Furthermore, calcofluor staining demonstrated that most of these cells formed two septa per cell and accumulated a large amount of chitin or its related polysaccharides around the septa. Closely similar phenotypes between hCRM1- and S. pombe Crm1-induced cells indicate that the cloned cDNA encodes a functional homolog of S. pombe crm1+. Northern blot analyses with RNAs isolated from synchronized mammalian cells showed that the expression of mammalian CRM1 was initiated in late G1 and reached a peak at G2/M, although its protein level unchanged during the cell cycle. Transient expression of hCRM1 fused to the green fluorescent protein (GFP) in NIH3T3 cells showed that hCRM1 was localized preferentially in the nuclear envelope and was also detectable in the nucleoplasm and the cytoplasm. A crm1 mutation of S. pombe caused nuclear import of a GFP fusion protein containing a nuclear export signal but no change in the distribution of a GFP fusion protein containing a nuclear localization signal. All of these data suggest that CRM1 is a novel cell-cycle regulated gene that is essential for the nuclear export signal-dependent nuclear export of proteins.


Different interactions of cardiac and skeletal muscle ryanodine receptors with FK-506 binding protein isoforms.
In the present study, we compare functional consequences of dissociation and reconstitution of binding proteins FKBP12 and FKBP12.6 with ryanodine receptors from cardiac (RyR2) and skeletal muscle (RyR1). The skeletal muscle RyR1 channel became activated on removal of endogenously bound FKBP12, consistent with previous reports. Both FKBP12 and FKBP12.6 rebind to FKBP-depleted RyR1 and restore its quiescent channel behavior by altering ligand sensitivity, as studied by single-channel recordings in planar lipid bilayers, and macroscopic behavior of the channels (ryanodine binding and net energized Ca2- uptake). By contrast, removal of FKBP12.6 from the cardiac RyR2 did not modulate the function of the channel using the same types of assays as for RyR1. FKBP12 or FKBP12.6 had no effect on channel activity of FKBP12.6-depleted cardiac RyR2, although FKBP12.6 rebinds. Our studies reveal important differences between the two ryanodine receptor isoforms with respect to their functional interaction with FKBP12 and FKBP12.6.


The recovery of function and microcirculation in small intestinal loops following ischaemia.
Short loops of dog small intestine, filled with a buffered glucose solution, were subjected to one hour's total ischaemia by clamping the corresponding mesenteric artery and vein as well as the intestinal wall at each end of the loop. Immediately after the ischaemic period and 24 hours later, their functional capacity, together with that of neighbouring control loops, was determined by studying the absorption of phenylalanine and beta-methyl-glucoside in vitro and by measuring the levels of Na(+)-K(+)-ATPase in the mucosa. The release of lysosomal enzymes after the ischaemia was studied by gauging the levels of acid phosphatase in the venous blood draining the ischaemic loop. The state of the mucosal microcirculation was investigated by injection of indian ink into the mesenteric artery removal of the loop. Immediately after ischaemia, considerable structural damage was observed in the intestinal mucosa, with desquamation of the villous tips, oedema, vascular stasis, and haemorrhagic infiltration in the lamina propria. No dye was observed in the mucosal capillaries. All transport capacity was abolished, but ATPase levels were unchanged. A significant release of lysosomal enzymes into the venous blood was noted. One day later structural and functional recovery was complete, and vascularization of the villous core was restored.


The impact of Medicare's Prospective Payment System on staffing of long-term acute care hospitals: the early evidence.
Long-term acute care hospitals (LTACHs) treat patients with complex medical conditions requiring hospital care for extended periods of time. In the last decade, Medicare saw spiraling costs for post-acute care settings. The Balanced Budget Act mandated the use of Prospective Payment System (PPS) for all post-acute care settings including LTACHs. Medicare shifted to PPS for LTACHs in October 2002. This study analyzes the early effect of Medicare's PPS on the staffing intensity of LTACHs. The study uses panel data of measures of hospital and market characteristics in years 2001 through 2004. The impact of the payment mechanism, market, and organizational variables on the staffing intensity of LTACHs is evaluated using fixed-effects (within-groups) regression analysis. The fixed-effects regression models found that Medicare's PPS was associated with higher staffing intensity of the LTACHs in years 2003 and 2004. Market-level per capita income was significantly positively associated with staffing intensity. No secular trend in staffing intensity was found. The concern that the cost containment incentives of PPS would result in lowered staffing levels of LTACHs was not borne out by this study. Further follow-up is required to assess in the longer term the effects of PPS on staffing and quality of care in LTACHs.


Multidisciplinary Oral Rehabilitation of a Severely Compromised Dentition.
The decision-making process of complex clinical cases should involve multiple specialists to obtain a predictable result on a long-term basis. In view of the above, the present report is aimed at describing the multidisciplinary management of a partially edentulous female patient presenting with a severely compromised residual dentition. To improve function and aesthetics, the treatment combined multiple extractions, temporary rehabilitation with a complete removable denture, guided bone regeneration and implant insertion, soft tissue management, tooth alignment, and restorative dentistry. Thus, several dental branches were embraced during the treatment phases, including oral surgery and implantology, periodontology, orthodontics, and prosthodontics. The involvement of different specialists ensured the achievement of a good result from biological, functional, and aesthetic aspects. The patient was satisfied with the final outcome. In conclusion, to meet the patient's expectations particularly in complex clinical situations, the interdisciplinary approach becomes essential from the early phases in order to identify the ideal treatment plan with the correct time sequence.


What should medical students be taught about abortion? An evaluation of student attitudes towards their abortion teaching and their future involvement in abortion care.
One in three women in the United Kingdom (UK) will have an abortion before age 45, making abortion provision an essential aspect of reproductive healthcare. Despite this, abortion remains ethically contested and stigmatised, with variable teaching in UK medical schools and concerns about falling numbers of doctors willing to participate in abortion care. University College London Medical School (UCLMS) has designed practical, inclusive, teaching that aims to give students an understanding of the importance of abortion care and prepare them to be competent practitioners in this area. This study aimed to determine students' opinions of this teaching and their wider attitudes towards abortion. We invited all 357 final-year UCL medical students to complete an online survey consisting of closed-ended questions, exploring their opinions on their abortion teaching, their personal beliefs about abortion and their future willingness to be involved in abortion care. We analysed responses using non-parametric tests. One hundred and forty-six questionnaires (41% response rate) showed 83% of students identified as pro-choice (agree with the right to choose an abortion). Fifty-seven percent felt they received the right amount of abortion teaching, 39% would have liked more and 4% stated they received too much. There was no correlation between students' attitudes to abortion and the rating of teaching; both pro-choice and pro-life (opposed to the right to choose an abortion) students generally rated the teaching as important and valued the range of methods used. Students requested more simulated practice speaking to patients requesting an abortion. Students with pro-life beliefs expressed lower willingness to discuss, refer, certify and provide future abortions. Students interested in careers in specialties where they may encounter abortion were more likely to be pro-choice than pro-life. The majority of participating UCL medical students were pro-choice and willing to be involved in future abortion care. Efforts to make teaching on abortion practical, engaging, sensitive and inclusive were appreciated. As well as preparing students to be competent and caring practitioners, the teaching appears to contribute towards them viewing abortion as an essential aspect of women's healthcare, and may contribute to destigmatising abortion.