[Weber-Christian disease].
In pursuance of the Federal law "On the fundamentals of health protection in RF", the Russian Ministry of Health approved the list of so-called orphan diseases, i.e. rare pathologies of great medical and social significance due to their life-threatening nature and immense burden on health budget. Weber-Christian disease is a chronic recurrent orphan diseases characterized by formation of painful dense nodes in subcutaneous fat free from suppuration and accompanied by episodic temperature changes, chill, muscular pain and sometimes damage to internal organs. The disease recurs at irregular intervals.


Sequential analysis of CD34+ and CD34- cell subsets in peripheral blood and leukapheresis products from breast cancer patients mobilized with SCF plus G-CSF and cyclophosphamide.
Administration of stem cell factor (SCF) has been proven to enhance cytokine-induced mobilization of CD34+ hematopoietic progenitor cells (HPC) into the peripheral blood (PB). The aim of the present study was to explore in a homogeneous group of 22 uniformly treated breast cancer patients: (1) the kinetics of mobilization into PB of both CD34+ and CD34- cell subsets, including dendritic cells, in sequential samples obtained from day +7 up to day +12 after mobilization; and (2) the composition of the CD34+ and CD34- cell subsets present in the two leukapheresis products obtained for each patient. The following CD34+ and CD34- subsets were analyzed: early CD34+ HPC, erythroid-, myeloid- and B-lymphoid-committed CD34+ precursor cells, mature T, B and NK cells, monocytes, neutrophils, eosinophils, basophils, and dendritic cells (DC) including three subsets of lin-/HLADR+DC (CD16+, CD33high and CD123high). Our results show that the absolute number of PB CD34+ HPC progressively increases from day +7 onwards. As far as the CD34- PB leukocyte subsets are concerned, monocytes (CD14+) displayed the earliest recovery after mobilization predicting neutrophil recovery 1 day in advance. The number of CD34+ HPC collected in a single leukapheresis product was always > or = 1.4 x 10(6) cells/kg body weight. No significant changes were observed between the two leukapheresis sessions either as regards their composition in CD34+ HPC subsets or their CD34- leukocyte populations except for a higher ratio of both CD34+ erythroid/CD34+ myeloid HPC (0.35 +/- 0.13 vs 0.30 +/- 0.13; P = 0.04) and neutrophils/monocytes (1.58 +/- 2.1 vs 0.69 +/- 0.27; P = 0.009) found for the first leukapheresis. Interestingly, the overall number of dendritic cells (DC) was higher in the second leukapheresis (1.06 +/- 0.56 vs 1.9 +/- 0.46; P = 0.02) due to a selective increase of the CD16+ antigen-presenting cells. In summary, our results show that the combination of cyclophosphamide, G-CSF and SCF is highly effective for stem cell mobilization, with differences observed in the mobilization kinetics of the different hematopoietic cell subsets analyzed.


Ultrathin two-dimensional atomic crystals as stable interfacial layer for improvement of lithium metal anode.
Stable cycling of lithium metal anode is challenging due to the dendritic lithium formation and high chemical reactivity of lithium with electrolyte and nearly all the materials. Here, we demonstrate a promising novel electrode design by growing two-dimensional (2D) atomic crystal layers including hexagonal boron nitride (h-BN) and graphene directly on Cu metal current collectors. Lithium ions were able to penetrate through the point and line defects of the 2D layers during the electrochemical deposition, leading to sandwiched lithium metal between ultrathin 2D layers and Cu. The 2D layers afford an excellent interfacial protection of Li metal due to their remarkable chemical stability as well as mechanical strength and flexibility, resulting from the strong intralayer bonds and ultrathin thickness. Smooth Li metal deposition without dendritic and mossy Li formation was realized. We showed stable cycling over 50 cycles with Coulombic efficiency ∼97% in organic carbonate electrolyte with current density and areal capacity up to the practical value of 2.0 mA/cm(2)and 5.0 mAh/cm(2), respectively, which is a significant improvement over the unprotected electrodes in the same electrolyte.


Sarcoidosis of the tentorium with cortical blindness.
Sarcoidosis rarely involves the visual system posterior to the chiasm. A 55-year-old woman presented with fluctuating bilateral macular-sparing homonymous hemianopsia. The computed tomographic scan revealed an extensive contrast-enhancing density involving the tentorium, posterior falx, and adjacent medial occipital lobes and cerebellum. Spinal fluid studies revealed a mixed cellular response, and a biopsy of the meninges established the diagnosis of sarcoidosis. Ultimately, vision was lost, despite chronic steroid therapy. The presumed mechanism of visual loss is infiltration of the occipital lobes by meningeal granulomas, possibly with coexistent vascular occlusion.


Idiopathic infertility in two captive male gerenuk (Litocranius walleri walleri).
Two adult male gerenuk (Litocranius walleri walleri) were confirmed infertile with distinctly varying clinical presentations. One animal had unilateral testicular degeneration/hypoplasia, and within 8 mo experienced atrophy/degeneration of the remaining testicle. The second animal had been previously treated with melengesterol acetate (MGA) milled in feed for 1 yr during puberty as part of an aggression-control study. The testes in this individual appeared normal both visually and on palpation; however, repeated semen collection consistently produced ejaculates containing high numbers of immotile spermatozoa, all of a single abnormal morphology: shortened tails, with normal total sperm counts for this species. Both gerenuk had cortisol concentrations within normal ranges for adult male gerenuk. Analysis of serum mineral concentration revealed zinc levels that would be considered low in domestic cattle. Testosterone levels were low for the animal discussed in case 1, but were within normal range for the animal in case 2 compared with other gerenuk. Investigations into endocrine causes, such as abnormal thyroid hormone concentrations and adrenal function, were unrewarding. Both animals discussed in this report are maternally related; therefore, a genetic cause of infertility cannot be ruled out. Further investigation into MGA, as well as the dietary zinc requirements for gerenuk, and resulting effects on spermatogenesis and testicular development are warranted.


On twitching motility and its mechanism.
Previously published reports have established a correlation between twitching motility and the possession of polar fimbriae in all cases examined. Twitching motility was shown to be highly dependent on the availability of liquid at the agar surface. In the present paper experiments are reported that establish: 1) the dependence of twitching on the existence of a layer of liquid of a particular thickness, 2) the production of such a liquid layer surrounding areas of growing organisms, and 3) the affinity of twitching bacteria for the air-water interface. Reasoning from these facts, it is postulated that the demonstrated affinity for the air-water interface is conferred upon the cells by the polar fimbriae. It is also suggested how the movements might be generated.


Curcumin and epithelial-mesenchymal transition in breast cancer cells transformed by low doses of radiation and estrogen.
Breast cancer is a major cause of global mortality in women. Curcumin exerts anti-proliferative, anti-migratory and apoptotic effects. The aim of this study was to evaluate gene expression involved in epithelial-mesenchymal transition (EMT). An in vitro model was developed with the MCF-10F immortalized breast epithelial cell line exposed to low radiation doses of high LET (linear energy transfer) α-particles (150 keV/µm) and cultured in the presence of 17β-estradiol (estrogen). The following cell lines were used: i) MCF-10F, normal; ii) Alpha5, pre-tumorigenic, and iii) Tumor2 derived from Alpha5 injected into the nude mice. Our previous results have shown that Alpha5 and Tumor2 increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice in comparison to control. Results indicated that curcumin decreased expression of EMT-related genes in Tumor2 cell line when compared to its counterpart as E-cadherin, N-cadherin, ZEB2, Twist1, Slug, Axl, vimentin, STAT-3, fibronectin; and genes p53 and caveolin-1, as well as apoptotic genes caspase-3, caspase-8, and others such as cyclin D1 and NFκB. All these changes induced a decrease in migratory and invasive capabilities of such a cell line. Thus, it seems that curcumin may impinge upon apoptosis and metastatic properties of the malignant cells exerting antitumor activity in breast cancer cells transformed by low doses of α-particles and estrogen in vitro.


Association of MicroRNA-146a and MicroRNA-149 Polymorphisms With Strokes in Asian Populations: An Updated Meta-Analysis.
Strokes are a major cause of disability and death worldwide. An association between microRNA-146a (miR-146a) and miR-149 polymorphisms and strokes was inconclusive. This meta-analysis aimed to reevaluate the strength of the association by searching online databases and retrieving relevant case-control studies published between 2000 and 2016. Nine articles including 8 on miR-146a rs2910164 G/C and 3 on miR-149 rs2292832 C/T in 3372 patients with stroke and 4394 controls were included. The miR-149 rs2292832 was significantly associated with the risk of a stroke under allelic (C vs T: odds ratio [OR] = 1.14; 95% confidence interval [CI] = 1.01-1.29; P = .03), homologous (CC vs TT: OR = 1.36; 95% CI = 1.05-1.77; P = .02), and recessive models (CC vs CT + TT: OR = 1.34; 95% CI = 1.05-1.71; P = .02). No correlation was detected between miR-146a rs2910164 and susceptibility to a stroke. In conclusion, the results suggested that miR-149 might be a risk factor for the development of a stroke, while miR-146a might not be. Well-designed studies with large populations are needed to clarify the association between miR-146a and miR-149 polymorphisms and strokes.


Fractionated radiolabeled antiferritin therapy for patients with recurrent Hodgkin's disease.
The objective of this study was to determine the therapeutic ratio of fractionated radiolabeled immunoglobulin therapy (RIT) for patients with recurrent Hodgkin's disease. Ninety patients with recurrent Hodgkin's disease received 2 mg of yttrium-90-labeled polyclonal rabbit antihuman ferritin IgG i.v. Fifty-seven patients received a single (unfractionated) administration per treatment cycle; 11 of them were treated with 0.3 mCi/kg body weight, 39 were treated with 0.4 mCi/kg body weight, and 7 received 0.5 mCi/kg body weight per treatment cycle. Thirty-three patients had their radiolabeled immunoglobulin administration separated (fractionated) in 2 x 0.25 mCi/kg body weight (total activity, 0.5 mCi/kg). The interval between fractions was 1 week. Radioimmunoconjugates did not cause serious acute side effects. In vivo radioimmunoconjugates were stable. Human antirabbit IgG antibodies were found in 2 of 50 retreated patients (<5%). Hematological toxicity was the only side effect noted in all patients, and it was usually temporary. Response rates (RRs) were 20%, 61%, and 86% after 0.3, 0.4, or 0.5 mCi/kg unfractionated yttrium-90-labeled antiferritin. The RR for patients treated with fractionated RIT was 42%. In the fractionated RIT group, complete responses were decreased, and progressive disease increased (P < 0.05). Complete responses had a medium duration of 6 months. Median survival times were 390 days for 1 x 0.4 mCi/kg and 300 days for the 2 x 0.25 mCi/kg patient group. Fractionation did not provide the expected decrease in hematological toxicity or the expected increase in tumor RRs.


Diversity of arthropods on Acacia mangium (Fabaceae) and production of this plant with dehydrated sewage sludge in degraded area.
Sewage sludge is an organic matter-rich material with abundant fractions of nitrogen and other macro and micronutrients, essential for plant growth and development such as Acacia mangium Willd. (Fabales: Fabaceae) used in recovering actions of degraded areas. The objective of this study was to evaluate over 24 months the abundance and diversity of chewing and pollinator insects and arthropod predators on A. mangium plants and the mass production and soil coverage by this plant, fertilized with dehydrated sewage sludge, in a degraded area. The experimental design was in randomized blocks with two treatments (with and without dehydrated sewage sludge) and 24 replications. The number of leaves per branch and branches per plant, defoliation percentage by chewing insects, soil cover and abundance of chewing and pollinator insects and arthropod predators were higher on A. mangium plants fertilized with dehydrated sewage sludge. Nasutitermes sp. (Blattodea: Termitidae) and Trigona spinipes F. (Hymenoptera: Apidae) were the most observed insects on trunks and leaves, respectively, of A. mangium plants fertilized with dehydrated sewage sludge. The A. mangium fertilization increases the populations of different insect and spider groups on this plant.


[Steroid hormones and pancreas: a new paradigm].
The relation between steroid hormones and pancreatic function has been poorly discussed and not very well understood. In general, there is a lack of recognition among the scientific community about the importance of steroids in pancreatic function (current paradigm). In the present article we present basic, as well as clinic and epidemiologic data that demonstrate steroid synthesis and steroid biotransformation by pancreatic tissue, how exocrine and endocrine functions are modulated by steroids, the gender specific frequency and behavior of some tumors and the use of synthetic steroids and steroid action antagonists as therapeutic agents. With the available information it is possible to establish that: 1. Pancreatic tissue synthesize and transform steroid hormones. 2. Pancreatic tissue respond to steroid hormones and express steroid specific receptor molecules. 3. Some endocrine functions such as insulin synthesis and release are modulated by steroids. 4. Tumor growth is modulated by steroids and anti-steroid drugs. This set of data creates a new paradigm for the holistic study of pancreas and opens new research fields. The application of this new paradigm might result in an increase in the knowledge of pancreatic physiology, in the design of new and better diagnostic methods and eventually in the design of more effective medical treatments for the pancreatic cancers.


The GM2 glycan serves as a functional coreceptor for serotype 1 reovirus.
Viral attachment to target cells is the first step in infection and also serves as a determinant of tropism. Like many viruses, mammalian reoviruses bind with low affinity to cell-surface carbohydrate receptors to initiate the infectious process. Reoviruses disseminate with serotype-specific tropism in the host, which may be explained by differential glycan utilization. Although α2,3-linked sialylated oligosaccharides serve as carbohydrate receptors for type 3 reoviruses, neither a specific glycan bound by any reovirus serotype nor the function of glycan binding in type 1 reovirus infection was known. We have identified the oligosaccharide portion of ganglioside GM2 (the GM2 glycan) as a receptor for the attachment protein σ1 of reovirus strain type 1 Lang (T1L) using glycan array screening. The interaction of T1L σ1 with GM2 in solution was confirmed using NMR spectroscopy. We established that GM2 glycan engagement is required for optimal infection of mouse embryonic fibroblasts (MEFs) by T1L. Preincubation with GM2 specifically inhibited type 1 but not type 3 reovirus infection of MEFs. To provide a structural basis for these observations, we defined the mode of receptor recognition by determining the crystal structure of T1L σ1 in complex with the GM2 glycan. GM2 binds in a shallow groove in the globular head domain of T1L σ1. Both terminal sugar moieties of the GM2 glycan, N-acetylneuraminic acid and N-acetylgalactosamine, form contacts with the protein, providing an explanation for the observed specificity for GM2. Viruses with mutations in the glycan-binding domain display diminished hemagglutination capacity, a property dependent on glycan binding, and reduced capacity to infect MEFs. Our results define a novel mode of virus-glycan engagement and provide a mechanistic explanation for the serotype-dependent differences in glycan utilization by reovirus.


Cognitive performance of premature infants: association between bronchopulmonary dysplasia and cognitive skills. Cross-sectional study.
Children born prematurely often have worse cognitive performance than those born at term regarding skills such as memory, attention and processing speed. Bronchopulmonary dysplasia may compromise cognitive development. The aims here were: a) To describe the cognitive performance of preterm infants with very low birth weight; b) To investigate its association with bronchopul-monary dysplasia adjusted for sociodemographic, neonatal and post-neonatal factors. Cross-sectional study developed in a public tertiary-care hospital. To evaluate cognition among 112 children, we applied an intelligence scale (Wechsler scale). The average scores for children with and without bronchopulmonary dysplasia were compared across the fve domains of the scale. Associations with bronchopulmonary dysplasia were investigated for domains that showed signifcant diferences between the two groups. Associations between exposure and outcome were estimated via multivariate logistic regression. There were no diferences in averages for the full-scale intelligence quotient, verbal intelligence quotient, performance intelligence quotient and general language composite domains. The processing speed quotient was the only domain that presented a signifcant diference between the two groups (P = 0.02). Among the children with bronchopulmonary dysplasia, low full-scale intelligence quotient was observed in 28.1%. In the multivariate analysis, bronchopulmonary dysplasia (odds ratio: 3.1; 95conf-dence interval: 1.1-8.7) remained associated with the outcome of processing speed quotient. Bronchopulmonary dysplasia was an independent risk factor for alteration of the processing speed quotient.


Reliability and validity of the Pragmatics Observational Measure (POM): a new observational measure of pragmatic language for children.
There is a need for a reliable and valid assessment of childhood pragmatic language skills during peer-peer interactions. This study aimed to evaluate the psychometric properties of a newly developed pragmatic assessment, the Pragmatic Observational Measure (POM). The psychometric properties of the POM were investigated from observational data of two studies - study 1 involved 342 children aged 5-11 years (108 children with ADHD; 108 typically developing playmates; 126 children in the control group), and study 2 involved 9 children with ADHD who attended a 7-week play-based intervention. The psychometric properties of the POM were determined based on the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) taxonomy of psychometric properties and definitions for health-related outcomes; the Pragmatic Protocol was used as the reference tool against which the POM was evaluated. The POM demonstrated sound psychometric properties in all the reliability, validity and interpretability criteria against which it was assessed. The findings showed that the POM is a reliable and valid measure of pragmatic language skills of children with ADHD between the age of 5 and 11 years and has clinical utility in identifying children with pragmatic language difficulty.


Stuck in the Middle With You: Why a Broad-Brush Approach to Defining Central Sensitization Does Not Help Clinicians and Patients.
Central sensitization is (1) increasingly interpreted as central nervous system hyperexcitability that accounts for a general increase in sensitivity, and (2) used to explain a variety of pain and nonpain symptoms. In this commentary, we argue that such a broad interpretation might not be clinically useful because it fails to distinguish one patient from another based on pathophysiological mechanisms and does not facilitate tailored treatment. We recommend that clinicians use a person-centered approach when assessing and managing patients, considering the different interacting processes/mechanisms that can contribute to a patient's clinical presentation. J Orthop Sports Phys Ther 2021;51(5):204-206. Epub 15 Mar 2021. doi:10.2519/jospt.2021.10340.


Evaluation of DGT techniques for measuring inorganic uranium species in natural waters: Interferences, deployment time and speciation.
Three adsorbents (Chelex-100, manganese dioxide [MnO(2)] and Metsorb), used as binding layers with the diffusive gradient in thin film (DGT) technique, were evaluated for the measurement of inorganic uranium species in synthetic and natural waters. Uranium (U) was found to be quantitatively accumulated in solution (10-100μgL(-1)) by all three adsorbents (uptake efficiencies of 80-99%) with elution efficiencies of 80% (Chelex-100), 84% (MnO(2)) and 83% (Metsorb). Consistent uptake occurred over pH (5-9), with only MnO(2) affected by pH<5, and ionic strength (0.001-1molL(-1) NaNO(3)) ranges typical of natural waters, including seawater. DGT validation experiments (5 days) gave linear mass uptake over time (R(2)≥0.97) for all three adsorbents in low ionic strength solution (0.01M NaNO(3)). Validation experiments in artificial sea water gave linear mass uptake for Metsorb (R(2)≥0.9954) up to 12h and MnO(2) (R(2)≥0.9259) up to 24h. Chelex-100 demonstrated no linear mass uptake in artificial sea water after 8h. Possible interferences were investigated with SO(4)(2-) (0.02-200mgL(-1)) having little affect on any of the three DGT binding layers. PO(4)(3-) additions (5μgL(-1)-5mgL(-1)) interfered by forming anionic uranyl phosphate complexes that Chelex-100 was unable to accumulate, or by directly competing with the uranyl species for binding sites, as with MnO(2) and the Metsorb. HCO(3)(-) (0.1-500mgL(-1)) additions formed anionic species which interfered with the performance of the Chelex-100 and the MnO(2), and the Ca(2+) (0.1-500mgL(-1)) had the affect of forming labile calcium uranyl species which aided uptake of U by all three resins. DGT field deployments in sea water (Southampton Water, UK) gave a linear mass uptake of U over time with Metsorb and MnO(2) (4 days). Field deployments in fresh water (River Lambourn, UK) gave linear uptake for up to 7 and 4 days for Metsorb and MnO(2) respectively. Field deployment of the Metsorb-DGT samplers with various diffusive layer thicknesses (0.015-0.175cm) allowed accurate measurements of the diffusive boundary layer (DBL) and allowed DBL corrected concentrations to be determined. This DBL-corrected U concentration was half that determined when the effect of the DBL was not considered. The ability of the DGT devices to measure U isotopic ratios with no isotopic fractionation was shown by all three resins, thereby proving the usefulness of the technique for environmental monitoring purposes.


Aspergillus Fumigatus ZnfA, a Novel Zinc Finger Transcription Factor Involved in Calcium Metabolism and Caspofungin Tolerance.
Invasive pulmonary aspergillosis is a life-threatening fungal infection especially in the immunocompromised patients. The low diversity of available antifungal drugs coupled with the emergence of antifungal resistance has become a worldwide clinical concern. The echinocandin Caspofungin (CSP) is recommended as a second-line therapy but resistance and tolerance mechanisms have been reported. However, how the fungal cell articulates the response to CSP is not completely understood. This work provides a detailed characterization of ZnfA, a transcription factor (TF) identified in previous screening studies that is involved in the A. fumigatus responses to calcium and CSP. This TF plays an important role in the regulation of iron homeostasis and cell wall organization in response to high CSP concentrations as revealed by Chromatin Immunoprecipitation coupled to DNA sequencing (ChIP-seq) analysis. Furthermore, ZnfA acts collaboratively with the key TF CrzA in modulating the response to calcium as well as cell wall and osmotic stresses. This study therefore describes the existence of an additional, previously unknown TF that bridges calcium signaling and the CSP cellular response and further exposes the complex connections that exist among different pathways which govern stress sensing and signaling in A. fumigatus.


Prevalence of Sarcopenia and Dynapenia and Related Clinical Outcomes in Patients with Type 1 Diabetes Mellitus.
Sarcopenia has recently been recognized as a complication of diabetes. However, there are few results about the prevalence of sarcopenia and dynapenia and the related clinical outcomes in type 1 diabetes mellitus (T1DM). Our objectives were to evaluate the prevalence of sarcopenia and dynapenia and to determine whether there are any associations with disease-related factors in people with T1DM. A cross-sectional study was conducted in people with T1DM. We assessed appendicular skeletal mass index (ASMI) using bioimpedance 50 Hz (Nutrilab Akern). Muscle function was assessed through handgrip strength (HGS) using a Jamar dynamometer. Sarcopenia was defined as a low HGS with low ASMI, whereas dynapenia was defined as low HGS with a normal ASMI. We used HGS data from the Spanish population percentile table and a cut-off point at p5 as dynapenia. The association of clinical, metabolic, and lifestyle variables with sarcopenia and dynapenia was studied. This study included 62 T1DM patients (66% females, mean age of 38 ± 14 years, body mass index (BMI) of 24.9 ± 4.7 kg/m2). The prevalence of sarcopenia and dynapenia was 8% and 23%, respectively. In our sample, there were more men in the sarcopenic and dynapenic groups. The sarcopenic group showed a significantly higher mean HbA1c value. Lower diabetes duration, PREDIMED score, BMI, and muscle mass measures (fat-free mass index (FFMI), ASMI, and body cell mass index (BCMI)) were significantly associated with sarcopenia. Decreased diabetes duration, PREDIMED score, phase angle (PhA), and HGS values showed a significant association with dynapenia. The prevalence of sarcopenia and dynapenia was high in people with T1DM in our study. Specifically, the proportion of dynapenia was quite high. HGS and ASMI are practical tools for the assessment of muscle health status in T1DM, and low values are associated with poor glycemic control, underweight, and low adherence to the Mediterranean diet. Thus, dynapenia may predict accelerated muscle aging in T1DM.


Branched grafts for thoracoabdominal aneurysms: off-label use of FDA-approved devices.
To report off-label use of approved off-the-shelf endografts with no modification to the devices for the management of thoracoabdominal aneurysms (TAAA). The parallel endograft octopus technique is demonstrated in a 68-year-old woman with a past history of open TAAA repair with a patch reimplant of the visceral vessels who now presented with back pain. Non-contrast computed tomography revealed a 6.8-cm aneurysm of the visceral segment involving the celiac trunk, superior mesenteric artery (SMA), and right renal artery. As she was at high risk for redo surgery due to significant pulmonary dysfunction, she was an ideal candidate for a branched graft, but she could not travel to an investigational site for a custom graft. At surgery, 4 sheaths were introduced, 2 retrograde (18-F DrySeal) and 2 (8-F) antegrade, via the femoral arteries. The 18-F sheaths on both sides were connected to the 8-F sheaths for continued limb perfusion. Via an axillary conduit, a 12-F, 80-cm sheath was introduced into the proximal thoracic aorta over a stiff wire. Subsequently, two 28-mm Excluder endografts were introduced via the bilateral 18-F femoral sheaths and positioned side by side in the descending thoracic aorta such that the lower end of the Excluder limbs were positioned ≥2 cm above the target visceral vessels. Viabahn stent-grafts were then deployed in the celiac axis, SMA, and right renal artery from the axillary conduit. Subsequently, a 23-mm Excluder was deployed within the distal end of the upsized limb and extended to both common iliac arteries. Imaging at 6 months demonstrated no endoleaks, with good flow to all visceral vessels. The parallel endograft octopus technique described here, which has been applied successfully in 9 cases thus far, is a relatively simple method using currently available devices with no requirement for device modification or customization. Although this technique shows promise, long-term data will be required to prove efficacy. This technique demonstrates a concept for future development of branched graft technology.


Ecological Factors Mediate Immunity and Parasitic Co-Infection in Sea Fan Octocorals.
The interplay among environment, demography, and host-parasite interactions is a challenging frontier. In the ocean, fundamental changes are occurring due to anthropogenic pressures, including increased disease outbreaks on coral reefs. These outbreaks include multiple parasites, calling into question how host immunity functions in this complex milieu. Our work investigates the interplay of factors influencing co-infection in the Caribbean sea fan octocoral, Gorgonia ventalina, using metrics of the innate immune response: cellular immunity and expression of candidate immune genes. We used existing copepod infections and live pathogen inoculation with the Aspergillus sydowii fungus, detecting increased expression of the immune recognition gene Tachylectin 5A (T5A) in response to both parasites. Cellular immunity increased by 8.16% in copepod infections compared to controls and single Aspergillus infections. We also detected activation of cellular immunity in reef populations, with a 13.6% increase during copepod infections. Cellular immunity was similar in the field and in the lab, increasing with copepod infections and not the fungus. Amoebocyte density and the expression of T5A and a matrix metalloproteinase (MMP) gene were also positively correlated across all treatments and colonies, irrespective of parasitic infection. We then assessed the scaling of immune metrics to population-level disease patterns and found random co-occurrence of copepods and fungus across 15 reefs in Puerto Rico. The results suggest immune activation by parasites may not alter parasite co-occurrence if factors other than immunity prevail in structuring parasite infection. We assessed non-immune factors in the field and found that sea fan colony size predicted infection by the copepod parasite. Moreover, the effect of infection on immunity was small relative to that of site differences and live coral cover, and similar to the effect of reproductive status. While additional immune data would shed light on the extent of this pattern, ecological factors may play a larger role than immunity in controlling parasite patterns in the wild. Parsing the effects of immunity and ecological factors in octocoral co-infection shows how disease depends on more than one host and one parasite and explores the application of co-infection research to a colonial marine organism.


Rapid regulation of pancreatic alpha- and beta- cell signalling systems by estrogens.
Rapid estrogen actions are triggered after estrogens are bound to a variety of proteins in organelles other than the nucleus. Those include classic estrogen receptors ERalpha and ERbeta, novel membrane proteins that behave as estrogen receptors such as GPR30, ion channels, and other ligand receptors. In pancreatic alpha and beta-cells, estrogens binding to a non-classical membrane estrogen receptors at physiological concentrations regulate ion channels and [Ca(2+)](i) signals, provoking important physiological responses. In beta-cells, 17beta-estradiol regulates K(ATP) channel activity and glucose-induced [Ca(2+)](i) oscillations, eliciting changes in insulin release and the activation of Ca(2+)-dependent transcription factors. In alpha-cells, 17beta-estradiol abolishes low glucose-induced [Ca(2+)](i) oscillations.


The transformation of cuboctahedral to icosahedral nanoparticles: atomic structure and dynamics.
The rearrangement of transition metal nanoparticles from cuboctahedral to icosahedral structures is studied for up to 923 atoms. The atomic structure and temperature dependence of the transition are investigated with a well-defined collective variable. This collective variable describes the folding of the square fcc(100) facets into two triangular facets through a linear combination of the diagonals of all fcc(100) facets of all shells of the particle. Activation barriers are determined through harmonic transition state theory and constrained molecular dynamics simulations based on force field potentials. These calculations predict an activation entropy larger than 1 meV K-1, leading to strongly temperature dependent activation barriers. Density functional theory calculations were additionally performed both as single point calculations and as full optimizations. Cu, Ag, Au and Ni clusters show low barriers for concerted, symmetric transition up to the 309-atomic clusters. In contrast, for Pd, Pt, Rh and Ir higher barriers are required, already for the 147-atomic clusters. With increasing barriers, an asymmetric but still concerted rearrangement becomes energetically more favorable than the fully symmetric transformation. The material-dependence of the transition can be correlated with the melting point of the bulk metals.


A simple model predicts experimental folding rates and a hub-like topology.
A simple model is presented that describes general features of protein folding, in good agreement with experimental results and detailed all-atom simulations. Starting from microscopic physics, and with no free parameters, this model predicts that protein folding occurs remarkably quickly because native-like states are kinetic hubs. A hub-like network arises naturally out of microscopic physical concerns, specifically the kinetic longevity of native contacts during a search of globular conformations. The model predicts folding times scaling as τ(f) ~ e(ξN) in the number of residues, but because the model shows ξ is small, the folding times are much faster than Levinthal's approximation. Importantly, the folding time scale is found to be small due to the topology and structure of the network. We show explicitly how our model agrees with generic experimental features of the folding process, including the scaling of τ(f) with N, two-state thermodynamics, a sharp peak in C(V), and native-state fluctuations.


The Juntos Pilot Study: A Diabetes Management Intervention for Latino Caregiving Dyads.
The purpose of this study was to design a culturally sensitive dyad-level diabetes intervention to improve glycemic control for older Latino adults with type 2 diabetes. This study used a pretest-posttest noncontrol group design. The intervention was developed from formative research with Mexican-origin caregiving dyads. The curriculum was adapted from 2 randomized trials of community interventions specifically designed for Latino older adults with type 2 diabetes. The curriculum consisted of communication skill-building exercises and dyad decision making on lifestyle changes to improve the older adult's blood glucose levels. Thirty-two community-dwelling dyads completed a 6-week program of one-on-one sessions with a trained program facilitator. Main outcomes were feasibility and acceptability of the Juntos program. The authors assessed feasibility by examining participant burden and retention and acceptability by participant exit interviews. Although underpowered for outcomes, A1C, health status, and dyadic communication were also assessed to evaluate whether trends suggested the effectiveness of the intervention. Most participants viewed Juntos as an acceptable program and wanted the program expanded in terms of length and scope. All outcomes showed improvement from baseline through 6 months postintervention. Results show that Juntos is acceptable to Mexican-origin caregiving dyads and is a promising approach for effectively controlling type 2 diabetes among older Latino adults who have a family caregiver.


Analysing ecological networks of species interactions.
Network approaches to ecological questions have been increasingly used, particularly in recent decades. The abstraction of ecological systems - such as communities - through networks of interactions between their components indeed provides a way to summarize this information with single objects. The methodological framework derived from graph theory also provides numerous approaches and measures to analyze these objects and can offer new perspectives on established ecological theories as well as tools to address new challenges. However, prior to using these methods to test ecological hypotheses, it is necessary that we understand, adapt, and use them in ways that both allow us to deliver their full potential and account for their limitations. Here, we attempt to increase the accessibility of network approaches by providing a review of the tools that have been developed so far, with - what we believe to be - their appropriate uses and potential limitations. This is not an exhaustive review of all methods and metrics, but rather, an overview of tools that are robust, informative, and ecologically sound. After providing a brief presentation of species interaction networks and how to build them in order to summarize ecological information of different types, we then classify methods and metrics by the types of ecological questions that they can be used to answer from global to local scales, including methods for hypothesis testing and future perspectives. Specifically, we show how the organization of species interactions in a community yields different network structures (e.g., more or less dense, modular or nested), how different measures can be used to describe and quantify these emerging structures, and how to compare communities based on these differences in structures. Within networks, we illustrate metrics that can be used to describe and compare the functional and dynamic roles of species based on their position in the network and the organization of their interactions as well as associated new methods to test the significance of these results. Lastly, we describe potential fruitful avenues for new methodological developments to address novel ecological questions.


Closure of the thoracic duct from the left-side access: A case report.
We report a 16-year-old patient with a massive left-sided chylothorax after chemotherapy due to mixed germinal tumor of the testis with massive metastases located in the retroperitoneal space and posterior mediastinum. Chemotherapy resolved the metastases in the mediastinum but evoked a huge pleural effusion in the left pleural cavity, requiring surgical intervention.Left-sided access was used. The 5-mm camera and 3 5-mm working ports were inserted. The parietal pleura was incised and the esophagus located and protected. Behind the esophagus, the thoracic duct and concomitant tissue were clipped with titanium clips, and additionally, thrombin glue was used. Stopping of the lymph leakage was observed during surgery. A local argon pleurodesis was used to finish the procedure. The thoracic tube was removed on the third postoperative day. Left-side access may be a good alternative in the left-sided chylothorax, but the crucial points are location and protection of the esophagus during the procedure, which is also the landmark that allows for locating the thoracic duct.


Using grounded theory methodology to conceptualize the mother-infant communication dynamic: potential application to compliance with infant feeding recommendations.
Excessive, rapid weight gain in early infancy has been linked to risk of later overweight and obesity. Inappropriate infant feeding practices associated with this rapid weight gain are currently of great interest. Understanding the origin of these practices may increase the effectiveness of interventions. Low-income populations in the Southeastern United States are at increased risk for development of inappropriate infant feeding practices, secondary to the relatively low rates of breastfeeding reported from this region. The objective was to use grounded theory methodology (GTM) to explore interactions between mothers and infants that may influence development of feeding practices, and to do so among low-income, primiparous, Southeastern United States mothers. Analysis of 15 in-depth phone interviews resulted in development of a theoretical model in which Mother-Infant Communication Dynamic emerged as the central concept. The central concept suggests a communication pattern developed over the first year of life, based on a positive feedback loop, which is harmonious and results in the maternal perception of mother and infant now speaking the same language. Importantly, though harmonious, this dynamic may result from inaccurate maternal interpretation of infant cues and behaviours, subsequently leading to inappropriate infant feeding practices. Future research should test this theoretical model using direct observation of mother-infant communication, to increase the understanding of maternal interpretation of infant cues. Subsequently, interventions targeting accurate maternal interpretation of and response to infant cues, and impact on rate of infant weight gain could be tested. If effective, health care providers could potentially use these concepts to attenuate excess rapid infant weight gain.


Human Adipose-Derived Stem Cells Labeled with Plasmonic Gold Nanostars for Cellular Tracking and Photothermal Cancer Cell Ablation.
Gold nanostars are unique nanoplatforms that can be imaged in real time and transform light energy into heat to ablate cells. Adipose-derived stem cells migrate toward tumor niches in response to chemokines. The ability of adipose-derived stem cells to migrate and integrate into tumors makes them ideal vehicles for the targeted delivery of cancer nanotherapeutics. To test the labeling efficiency of gold nanostars, undifferentiated adipose-derived stem cells were incubated with gold nanostars and a commercially available nanoparticle (Qtracker), then imaged using two-photon photoluminescence microscopy. The effects of gold nanostars on cell phenotype, proliferation, and viability were assessed with flow cytometry, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide metabolic assay, and trypan blue, respectively. Trilineage differentiation of gold nanostar-labeled adipose-derived stem cells was induced with the appropriate media. Photothermolysis was performed on adipose-derived stem cells cultured alone or in co-culture with SKBR3 cancer cells. Efficient uptake of gold nanostars occurred in adipose-derived stem cells, with persistence of the luminescent signal over 4 days. Labeling efficiency and signal quality were greater than with Qtracker. Gold nanostars did not affect cell phenotype, viability, or proliferation, and exhibited stronger luminescence than Qtracker throughout differentiation. Zones of complete ablation surrounding the gold nanostar-labeled adipose-derived stem cells were observed following photothermolysis in both monoculture and co-culture models. Gold nanostars effectively label adipose-derived stem cells without altering cell phenotype. Once labeled, photoactivation of gold nanostar-labeled adipose-derived stem cells ablates neighboring cancer cells, demonstrating the potential of adipose-derived stem cells as a vehicle for the delivery of site-specific cancer therapy.


The Relationship of Self-Control and Abstinence Maintenance: An Exploratory Analysis of Self-Regulation.
Studies of self-regulation suggested that self-control requires finite resources which, in turn, may present a significant challenge for those trying to recover from or control addictive behaviors. The present study examined the relationships between self-regulation and abstinence maintenance among adults in recovery (n = 606: 407 men, 199 women; M age = 38.5 years) residing in self-governed, communal living, abstinent homes across the United States. Self-regulation scores (controlling for sex and age) were positively related to length of abstinence. In addition, a factor analysis of self-regulation scores resulted in some differentiation between general self-discipline and impulsivity in self-control related to addiction. The relationship between impulsivity and length of abstinence was stronger than the relationship derived between general self-regulation and length of abstinence.


Gene ORGANizer: linking genes to the organs they affect.
One of the biggest challenges in studying how genes work is understanding their effect on the physiology and anatomy of the body. Existing tools try to address this using indirect features, such as expression levels and biochemical pathways. Here, we present Gene ORGANizer (geneorganizer.huji.ac.il), a phenotype-based tool that directly links human genes to the body parts they affect. It is built upon an exhaustive curated database that links >7000 genes to ∼150 anatomical parts using >150 000 gene-organ associations. The tool offers user-friendly platforms to analyze the anatomical effects of individual genes, and identify trends within groups of genes. We demonstrate how Gene ORGANizer can be used to make new discoveries, showing that chromosome X is enriched with genes affecting facial features, that positive selection targets genes with more constrained phenotypic effects, and more. We expect Gene ORGANizer to be useful in a variety of evolutionary, medical and molecular studies aimed at understanding the phenotypic effects of genes.


Scurvy: A Neglected Cause of Muscle Pain and Weakness in a Child With Picky Eating Behavior.
Ascorbic acid (vitamin C) is an essential micronutrient that the human's body cannot synthesize endogenously. Scurvy, a disease of ascorbic acid deficiency, can manifest in a myriad of presentations. Due to its rarity in the modern world, scurvy is considered as a disease of the past. We present a paediatric case of scurvy with musculoskeletal manifestations as a result of picky eating behavior. We report a previously healthy nine-year-old boy who presented with unexplained progressive bilateral lower limb generalized weakness and pain for two months. All initial biochemical and radiological investigations were unremarkable. Upon further history taking, he had severe picky eating behavior which raised the suspicion of scurvy. The diagnosis was confirmed with a serum ascorbic acid test. After ascorbic acid supplementation, his symptoms resolved immediately. Further food behavioral modification counselling to his family members helped to change his diet in a lasting way. As a result, he had no recurrence of symptoms. This case highlights the importance of having a high index of suspicion for an uncommon disease and emphasizes the need for a detailed dietary history upon patient's presentation.


Hospitalization for initiation of maintenance hemodialysis.
Recent data on complications of hemodialysis (HD) is lacking. With advancement in dialysis technology the incidence of complications such as dialysis disequilibrium syndrome (DDS) has decreased. Notwithstanding these improvements many patients with end-stage renal disease (ESRD) continue to be hospitalized solely for initiation of hemodialysis. This study was undertaken to assess if such admissions are justified and also to determine incidence and predictors of complications of HD during initiation. Medical records of adult patients (>18 years) initiated on maintenance hemodialysis from January 1st, 1998 through December 31st, 2000 at our institution were reviewed. The demographics of the patients, cause of renal failure, creatinine clearance, type of vascular access, comorbidities, serum chemistries, ultrafiltration (UF) rate and indications for initiating dialysis were noted. Intradialytic complications were retrieved from the dialysis flow sheets. Of the 240 patients reviewed, 18.3% developed complications during initiation of dialysis, and none was severe. Hypotension and leg cramps were the most frequent complications. The patients who developed hypotension and cramps were significantly older than those with no complications, 57.7 +/- 14.9 (mean +/- SD) years versus 52.3 +/- 14.8 years, respectively (p = 0.02). The increment of age significantly influenced the complication rate [odds ratio (OR): 1.03, 95% confidence interval (CI) 1.01-1.05 (p = 0.03)], and so did hematocrit (HCT) (OR: 1.07, 95% CI 1.01-1.13). Multivariate analysis using age and hematocrit as continuous variables revealed that the older patients with anemia had a significantly higher risk of developing HD related complications than younger patients with anemia (OR: 1.05, 95% CI 1.01-1.09 at HCT of 24%, and OR: 1.03, 95% CI 1.00-1.06 at HCT 27%). When patients were stratified by hematocrit level, older patients with hematocrit <27% had higher risk of complications and the risk increased with increasing age [complication rate (HCT <27%): age <40 = 0%, age 40-64 = 11.7%, age >65 = 25%, p < 0.016]. Although very few, hypotension and muscle cramps were the main complications during initiation of HD. Older patients with anemia are prone for these complications although no physician intervention was necessary. Hospitalization solely for initiation of maintenance dialysis is not necessary and the additional cost from such admissions cannot be justified.


The practice of rectal examination.
Rectal (both digital and rigid sigmoidoscopic) examination is an important part of the clinical examination. The aim of this study was to find out the opinions of the patients to this routine examination at the time of referral by their general practitioner and during their first hospital interview. Assessment of the value for the rectal examination was also examined. We questioned 103 patients attending their second out-patient interview through a simple questionnaire. We discovered that patients considered awareness and explanation important: patients preferred to be told of the possibility of rectal examination prior to hospital consultation. Explanation of the method and reason was expected from hospital doctors. Formal consent was expected; informed verbal consent should be sufficient. Where logistically possible, a chaperone should always be present. Rectal examination would have facilitated the diagnosis in 47% of the patients examined. Thus, rectal examination should be performed on all patients where symptoms are referable to the lower gastrointestinal tract and where a possible diagnosis may be made or facilitated.


[Multiple trauma and burns].
Patients with multiple injuries and burns are the paradigm of critically-ill patients. Their cases are acute, severe and, fortunately, reversible in a large number of situations. The severe aggressions leading to this kind of condition is the rigger for a maelstrom of inflammatory mediators, metabolic and neuro-endocrinal response, leading to an acceleration in the combustion of the injured organ. This "internal combustion" process takes nourishment from organic reserves, using them up and thus producing dysfunctions in various organs. This is where nutritional support has a role, always remedying the metabolic response to inflammation and attempting to modify it. For this reason, nutritional support plays an undisputed part in the treatment of such patients. This nutritional support, so necessary in situations with a high degree of stress, must be individually tailored in terms of quantity and quality to the process and to the patient in question. Thus, adapting the support to requirements appears as a priority of nutritional assessment. While it is important to provide nourishment to needy patients, it is just as important if not more so to avoid over-nourishment. Indirect calorimetry continues to be the most accurate indicator for determining the needs of each patient and, in view of the lack of knowledge of this technique mainly as a result of economic factors, many different methods and formulas have been proposed to attempt to carry out these adjustments. The characteristics and distribution of the macronutrients will be connected with the pathologies to be treated. And finally, the route for providing this nourishment seems ever more clearly to be as prompt first-line administration through the digestive tube. There are situations in which parenteral support will complement or replace the enteral route when the latter is insufficient or unavailable; in certain circumstances, the parenteral route even seems to be superior to enteral support, as in the case of pure head injury. As these patients are particularly prone to suffer from infections, another aspect of increasing interest in the nutritional support of these patients is the use of immunity-modulating diets, where a better response can be expected. The components of the immunity-modulating diets have been shown to be able to modify the immune response in different ways, sometimes favouring the replication of lymphocytes and at other times stimulating the production of certain types of cytokines and attenuating the release of others, in short balancing the inflammatory response.


Inducible genetic lineage tracing of cortical hem derived Cajal-Retzius cells reveals novel properties.
During cortical development, Cajal-Retzius (CR) cells are among the earliest-born subclasses of neurons. These enigmatic neurons play an important role in cortical development through their expression of the extracellular protein, reelin. CR cells arise from discrete sources within the telencephalon, including the pallial-subpallial border and the medial (cortical hem) regions of the pallium. Combined evidence suggests that CR cells derived from distinct origins may have different distributions and functions. By tracing CR cells derived from the cortical hem using the inducible Cre transgenic mouse tool, Frizzled 10-CreER™, we examined the specific properties of hem-derived CR cells during cortical development. Our results show that the progenitor zone for later production of CR cells from the hem can be specifically marked as early as embryonic day 6.5 (E6.5), a pre-neural period. Moreover, using our Cre line, we found that some hem-derived CR cells migrated out along the fimbrial radial glial scaffold, which was also derived from the cortical hem, and preferentially settled in the hippocampal marginal zone, which indicated specific roles for hem-derived CR cells in hippocampal development.


Leptin actions on the reproductive neuroendocrine axis in sheep.
There is a growing literature on the role of leptin in appetite and neuroendocrine regulation in domestic ruminants. Circulating leptin concentration is higher in fat than in thin sheep, is reduced by chronic underfeeding and is higher in sheep subjected to long-day rather than short-day photoperiods. Leptin is reduced acutely by fasting and increases after meals so that there are long- and short-term components to the systemic leptin signal. Nutritional stimulation of reproductive neuroendocrine output is associated with increased circulating concentrations of leptin; peripheral leptin administration restores LH secretion in fasted sheep, and leptin is permissive (although not a trigger) for puberty. Intracerebroventricular (i.c.v.) pharmacological leptin infusion stimulates LH in underfed but not in well-fed sheep, and reduces food intake in well-fed sheep. A single i.c.v. pharmacological injection or physiological infusion of leptin stimulates LH in well-fed sheep, with or without a concomitant decrease in appetite. Furthermore, these appetite and LH responses are differentially affected by photoperiod, indicating that different neuronal pathways may mediate the two responses. Hypothalamic leptin receptors co-localize with orexigenic and anorexigenic neurones, some of which contact GnRH cells, but the confluence of leptin signalling with photoperiod (melatonin) signalling remains unresolved. Photoperiod-entrained sheep provide potential models of altered central leptin sensitivity, in which downstream mechanisms regulating appetite and GnRH may be dissociated.


Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions.
The mouth and oropharynx are among the ten most common sites affected by cancer worldwide, but global incidence varies widely. Five-year survival rates exceed 50% in only the best treatment centers. Causes are predominantly lifestyle-related: Tobacco, areca nut, alcohol, poor diet, viral infections, and pollution are all important etiological factors. Oral cancer is a disease of the poor and dispossessed, and reducing social inequalities requires national policies co-ordinated with wider health and social initiatives - the common risk factor approach: control of the environment; safe water; adequate food; public and professional education about early signs and symptoms; early diagnosis and intervention; evidence-based treatments appropriate to available resources; and thoughtful rehabilitation and palliative care. Reductions in inequalities, both within and between countries, are more likely to accrue from the application of existing knowledge in a whole-of-society approach. Basic research aimed at determining individual predisposition and acquired genetic determinants of carcinogenesis and tumor progression, thus allowing for targeted therapies, should be pursued opportunistically.


Susceptibility to bacterial sepsis. Accurate measurement by the delayed-type hypersensitivity skin test score.
To test the hypothesis that any alteration in the delayed-type hypersensitivity (DTH) skin test response (not necessarily total anergy) reflects increased susceptibility to bacterial sepsis, male Sprague-Dawley rats presensitized to keyhole-limpet hemocyanin were subjected to a 30% full-thickness scald burn. Susceptibility to bacteria was assessed by the intradermal injection of Staphylococcus aureus 502A. The DTH response decreased following burn injury from 6.6 to 3.9 mm on days 2 and 8. Skin abscess size increased from 5.8 to 9.3 mm on day 2 and 8.9 mm on day 8. There was a significant inverse correlation between DTH skin test score and abscess size. Histologically there was no difference in the overall leukocyte accumulation in the abscess or the DTH reaction between the two groups, yet the overall size of the abscess was greater and the swelling of the dermis in the DTH response was less in the burned rats.


Reporting Clinical End Points and Safety Events in an Acute Coronary Syndrome Trial: Results With Integrated Collection.
End points and adverse events (AEs) are collected separately in clinical trials, yet regulatory requirements for serious AE reporting vary across regions, so classifying end points according to seriousness criteria can be useful in global trials. In the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial, patients with a recent acute coronary syndrome were randomized to apixaban or placebo for the prevention of recurrent ischemic events. Suspected end points (myocardial infarction, stroke, or bleeding) were adjudicated by an independent clinical events classification committee. Safety criteria were collected for suspected end points and AEs. Patient-level event rates per 100 patient-days of follow-up, modeled using Poisson regression, explored the influence of region and patient characteristics on event reporting. Overall, 13 909 events were reported by 858 sites in 39 countries; 8.4% (n=1166) were suspected end points, and 91.6% (n=12 743) were AEs. Overall, 66.0% of suspected end points were confirmed by the clinical events classification committee. Most clinical events classification committee-confirmed end points met criteria to be classified as serious (94.0%); many clinical events classification committee-negated end points also did (63.2%), but fewer AEs met seriousness criteria (17.9%). The most common seriousness criterion was hospitalization (79.9%, n=2594). Region explained 28.7% of end point- and 26.4% of serious AE-reporting variation, and patient characteristics explained an additional 25.4% of end point and 13.4% of serious AE variation. Nonserious AE-reporting variation was not explained by adjustment. An integrated collection of end points and serious AEs is feasible in a multinational trial and illustrates the shared characteristics of events. Tailoring event collection to fit the phase and purpose of the trial is achievable and informative. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00831441.


Nonacademic Attributes Predict Medical and Nursing Student Intentions to Emigrate or to Work Rurally: An Eight-Country Survey in Asia and Africa.
AbstractWe sought to identify independent, nonacademic predictors of medical and nursing student intent to migrate abroad or from rural to urban areas after graduation in low- and middle-income countries (LMIC). This was a cross-sectional survey of 3,199 first- and final-year medical and nursing students at 16 training institutions in eight LMIC. Questionnaires assessed demographics, career intentions, and preferences regarding selected career, location, and work-related attributes. Using principal component analysis, student preferences were reduced into four discrete categories of priorities: 1) work environment resources, 2) location livability, 3) altruistic job values, and 4) individualistic job values. Students' preferences were scored in each category. Using students' characteristics and priority scores, multivariable proportional odds models were used to derive independent predictors of intentions to emigrate for work outside the country, or to work in a rural area in their native country. Students prioritizing individualistic values more often planned international careers (adjusted odds ratio [aOR] = 1.44, 95% confidence interval [CI] = 1.16-1.78), whereas those prioritizing altruistic values preferred rural careers (aOR = 1.82, 95% CI = 1.50-2.21). Trainees prioritizing high-resource environments preferentially planned careers abroad (aOR = 1.38, 95% CI = 1.12-1.69) and were unlikely to seek rural work (aOR = 0.60, 95% CI = 0.49-0.73). Independent of their priorities, students with prolonged prior rural residence were unlikely to plan emigration (aOR = 0.67, 95% CI = 0.50-0.90) and were more likely to plan a rural career (aOR = 1.53, 95% CI = 1.16-2.03). We conclude that use of nonacademic attributes in medical and nursing admissions processes would likely increase retention in high-need rural areas and reduce emigration "brain drain" in LMIC.


Direct sequencing of haplotypes from diploid individuals through a modified emulsion PCR-based single-molecule sequencing approach.
While standard DNA-sequencing approaches readily yield genotypic sequence data, haplotype information is often of greater utility for population genetic analyses. However, obtaining individual haplotype sequences can be costly and time-consuming and sometimes requires statistical reconstruction approaches that are subject to bias and error. Advancements have recently been made in determining individual chromosomal sequences in large-scale genomic studies, yet few options exist for obtaining this information from large numbers of highly polymorphic individuals in a cost-effective manner. As a solution, we developed a simple PCR-based method for obtaining sequence information from individual DNA strands using standard laboratory equipment. The method employs a water-in-oil emulsion to separate the PCR mixture into thousands of individual microreactors. PCR within these small vesicles results in amplification from only a single starting DNA template molecule and thus a single haplotype. We improved upon previous approaches by including SYBR Green I and a melted agarose solution in the PCR, allowing easy identification and separation of individually amplified DNA molecules. We demonstrate the use of this method on a highly polymorphic estuarine population of the copepod Eurytemora affinis for which current molecular and computational methods for haplotype determination have been inadequate.


Two-photon neuronal and astrocytic stimulation with azobenzene-based photoswitches.
Synthetic photochromic compounds can be designed to control a variety of proteins and their biochemical functions in living cells, but the high spatiotemporal precision and tissue penetration of two-photon stimulation have never been investigated in these molecules. Here we demonstrate two-photon excitation of azobenzene-based protein switches and versatile strategies to enhance their photochemical responses. This enables new applications to control the activation of neurons and astrocytes with cellular and subcellular resolution.


Heightened attentional capture by visual food stimuli in anorexia nervosa.
The present study was designed to test the hypothesis that anorexia nervosa (AN) patients are relatively insensitive to the attentional capture of visual food stimuli. Attentional avoidance of food might help AN patients to prevent more elaborate processing of food stimuli and the subsequent generation of craving, which might enable AN patients to maintain their strict diet. Participants were 66 restrictive AN spectrum patients and 55 healthy controls. A single-target rapid serial visual presentation task was used with food and disorder-neutral cues as critical distracter stimuli and disorder-neutral pictures as target stimuli. AN spectrum patients showed diminished task performance when visual food cues were presented in close temporal proximity of the to-be-identified target. In contrast to our hypothesis, results indicate that food cues automatically capture AN spectrum patients' attention. One explanation could be that the enhanced attentional capture of food cues in AN is driven by the relatively high threat value of food items in AN. Implications and suggestions for future research are discussed. (PsycINFO Database Record


The contribution of epigenetics in Sjögren's Syndrome.
Sjögren's syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers.


"If you work alone on this project, you can't reach your target": unpacking the leader's role in well-performing teams in a maternal and neonatal quality improvement programme in South Africa, before and during COVID-19.
The South African National Department of Health developed a quality improvement (QI) programme to reduce maternal and neonatal mortality and still births. The programme was implemented between 2018 and 2022 in 21 purposively selected public health facilities. We conducted a process evaluation to describe the characteristics and skills of the QI team leaders of well-performing teams. The evaluation was conducted in 15 of the 21 facilities. Facilities were purposively selected and comprised semi-structured interviews with leaders at three time points; reviewing of QI documentation; and 37 intermittently conducted semi-structured interviews with the QI advisors, being QI technical experts who supported the teams. These interviews focused on participants' experiences and perceptions of how the teams performed, and performance barriers and enablers. Thematic data analysis was conducted using Atlas.ti. Variation in team performance was associated with leaders' attributes and skills. However, the COVID-19 pandemic also affected team functioning. Well-performing teams had leaders who effectively navigated COVID-19 and other challenges, who embraced QI and had sound QI skills. These leaders cultivated trust by taking responsibility for failures, correcting members' mistakes in encouraging ways, and setting high standards of care. Moreover, they promoted programme ownership among members by delegating tasks. Given the critical role leaders play in team performance and thus in the outcomes of QI programmes, efforts should focus on leader selection, training, and support.


Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury.
Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1-LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury. This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury.


Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD.
Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised. Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-γ, interleukin (IL)-4, tumour necrosis factor (TNF)-α and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry. We found significantly increased proportions of IFN-γ+ and TNF-α+ CD8+ T-cells in COPD patients, when compared with healthy controls. This was most evident in patients with less severe disease. In contrast, expression profiles in circulating CD4+ T-cells were similar in COPD patients and healthy controls for all cytokines tested, except for IL-17F. COPD patients with more severely reduced diffusing capacity had lower proportions of IL-17A+ CD4+ T-cells. Proportions of IL-22+ cells in the CD4+ memory T-cell population were significantly increased in active smokers, when compared with past smokers. Collectively, this comprehensive cytokine analysis of circulating T-cells in COPD patients revealed a correlation for CD8+ T-cells between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and IFN-γ or TNF-α expression, but not for CD4+ T-cells.


Leveling of Tuberculosis Incidence - United States, 2013-2015.
After 2 decades of progress toward tuberculosis (TB) elimination with annual decreases of ≥0.2 cases per 100,000 persons (1), TB incidence in the United States remained approximately 3.0 cases per 100,000 persons during 2013-2015. Preliminary data reported to the National Tuberculosis Surveillance System indicate that TB incidence among foreign-born persons in the United States (15.1 cases per 100,000) has remained approximately 13 times the incidence among U.S.-born persons (1.2 cases per 100,000). Resuming progress toward TB elimination in the United States will require intensification of efforts both in the United States and globally, including increasing U.S. efforts to detect and treat latent TB infection, strengthening systems to interrupt TB transmission in the United States and globally, accelerating reductions in TB globally, particularly in the countries of origin for most U.S.


Characterization of bacteriophages from tox-containing, non-toxigenic isolates of Corynebacterium diphtheriae.
Non-toxigenic strains of Corynebacterium diphtheriae continue to cause disease within immunized populations. A subset of these corynebacteria carry the diphtheria toxin gene but in a cryptic form. To determine whether such strains might contribute to the re-emergence of functional toxin genes, the phages and tox mutations within three clone types were examined. tox-containing, beta-related phages were isolated from two of the strain types. The third isolate appeared to harbour a defective prophage. One of the tox- phages encoded truncated, yet enzymatically-active, forms of diphtheria toxin, suggesting that it had sustained a point mutation within the latter half of its toxin gene. In contrast, the other mutant phage did not elicit the production of either a cross-reacting material or an ADP-ribosylating activity. Complementation tests employing a series of double lysogens confirmed that the mutations responsible for the non-toxigenic phenotype of all of the phages were cis dominant. Given these findings, it is reasonable to hypothesize that tox+ genes can arise within human populations by either homologous recombination between two distinct tox- phages or spontaneous reversion within a single mutant allele.


Neural activity in SII modifies sensory evoked potentials in SI in awake rats.
The function of the projection from the secondary somatosensory cortex (SII) to the primary somatosensory cortex (SI) in rats was investigated by recording sensory evoked potentials (SEP) in SI during glutamate activation and lidocaine blockade of SII. In anesthetized animals, glutamate stimulation of SII decreased SEP latency and increased SEP amplitude, whereas no changes were evident during lidocaine blockade of SII. In awake animals, a second, later component of the SEP appeared. This second component was almost completely eliminated during lidocaine blockade of SII. We conclude that the projection from SII to SI in rats slightly facilitates the SEP response in anesthetized animals and is responsible for a major portion of the late component of the SEP in awake animals.


Ultrastructural localization of fibronectin and laminin in the basement membranes of the murine kidney.
Affinity-purified rabbit antibodies specific for two large noncollagenous gycoproteins--laminin and fibronectin--were used to study the distribution of these proteins in normal murine kidneys. Immunofluorescence staining of conventional frozen sections demonstrates fibronectin within mesangial areas of the glomerulus. Laminin is also found in mesangial areas. However, it also appears to be distributed in typical basement membranelike patterns on glomerular and tubular basement membranes and Bowman's capsule. At the ultrastructural level, by labeling 600-800-A thick frozen sections with a three-stage procedure consisting of specific antibodies, biotinyl sheep anti-rabbit IgG, and avidin-ferritin conjugates, fibronectin is present ony in the mesangial matrix and is specifically localized to areas immediately surrounding mesangial cell processes. Laminin, on the other hand, is found uniformly distributed throughout tubular basement membranes, the mesangial matrix, and Bowman's capsule. In glomerular basement membranes, laminin labeling is restricted to the lamina rara interna and adjacent regions of the lamina densa.


Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma.
Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.


Stride frequency and ventilation at constant carbon dioxide output.
To determine the consequences of two different stride frequencies on ventilation (VE) at similar levels of carbon dioxide production (VCO2), eleven male subjects performed two work tests on the treadmill. One test involved walking at a speed of 5 km/hr on a 15% grade while the other consisted of running on the treadmill at 9 km/hr on a 0% grade. Running increased stride frequency by 47%. The running and walking tests resulted in similar VCO2 levels, 1.85 +/- .18 and 1.9 +/- .20 l/min respectively, a non-significant difference. Ventilation during running was 43.73 +/- 6.51 l/min and during walking was 43.26 +/- 6.79 l/min, a non-significant difference. In addition the time constants for oxygen consumption (VCO2), VE and VCO2 were measured. The time constants for VCO2 and VE were not found to differ significantly during either the running or walking test. From our results, it can be seen that VE is more closely aligned to the metabolic state rather than stride frequency. In addition, the coupling of VE and VCO2 during the non-steady state is further indicative that ventilation is linked to the metabolic demands of the body.


CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer.
Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers. We determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays. The identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively). CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.


High-power, multioutput piezoelectric transformers operating at the thickness-shear vibration mode.
In this study, a piezoelectric transformer operating at the thickness shear vibration mode and with dual or triple outputs is proposed. It consists of a lead zirconate titanate (PZT) ceramic plate with a high mechanical quality factor Qm and a size of 120 x 20 x 4 mm3. The PZT ceramic plate is poled along the width direction. The electrodes of input and output parts are on the top and bottom surfaces of the ceramic plate and separated by narrow gaps. A new construction of support and lead wire connection is used for the transformer. At a temperature rise less than 20 degrees C and efficiency of 90%, the piezoelectric transformer with dual outputs has a maximum total output power of 169.8 W, with a power of 129.5 W in one output and 40.3 W in another. The one with triple outputs has a maximum total output power of 163.1 W, with a power of 36.9 W in the first output, 13.0 W in the second output and 113.2 W in the third output. The maximum efficiency of the piezoelectric transformer with dual outputs and triple outputs is 98% and 95.7%, respectively. The voltage gains of the transformers are less than one, and different outputs have different gains. Also, there is a driving frequency range in which the load resistance of one output has little effect on the voltage gain of another output.


Clostridium scindens exacerbates experimental necrotizing enterocolitis via upregulation of the apical sodium-dependent bile acid transporter.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Evidence indicates that bile acid homeostasis is disrupted during NEC: ileal bile acid levels are elevated in animals with experimental NEC, as is expression of the apical sodium-dependent bile acid transporter (Asbt). In addition, bile acids, which are synthesized in the liver, are extensively modified by the gut microbiome, including via the conversion of primary bile acids to more cytotoxic secondary forms. We hypothesized that the addition of bile acid-modifying bacteria would increase susceptibility to NEC in a neonatal rat model of the disease. The secondary bile acid-producing species Clostridium scindens exacerbated both incidence and severity of NEC. C. scindens upregulated the bile acid transporter Asbt and increased levels of intraenterocyte bile acids. Treatment with C. scindens also altered bile acid profiles and increased hydrophobicity of the ileal intracellular bile acid pool. The ability of C. scindens to enhance NEC requires bile acids, as pharmacological sequestration of ileal bile acids protects animals from developing disease. These findings indicate that bile acid-modifying bacteria can contribute to NEC pathology and provide additional evidence for the role of bile acids in the pathophysiology of experimental NEC.NEW & NOTEWORTHY Necrotizing enterocolitis (NEC), a life-threatening gastrointestinal emergency in premature infants, is characterized by dysregulation of bile acid homeostasis. We demonstrate that administering the secondary bile acid-producing bacterium Clostridium scindens enhances NEC in a neonatal rat model of the disease. C. scindens-enhanced NEC is dependent on bile acids and driven by upregulation of the ileal bile acid transporter Asbt. This is the first report of bile acid-modifying bacteria exacerbating experimental NEC pathology.


Marker-free quantification of repair pathway utilization at Cas9-induced double-strand breaks.
Genome integrity and genome engineering require efficient repair of DNA double-strand breaks (DSBs) by non-homologous end joining (NHEJ), homologous recombination (HR), or alternative end-joining pathways. Here we describe two complementary methods for marker-free quantification of DSB repair pathway utilization at Cas9-targeted chromosomal DSBs in mammalian cells. The first assay features the analysis of amplicon next-generation sequencing data using ScarMapper, an iterative break-associated alignment algorithm to classify individual repair products based on deletion size, microhomology usage, and insertions. The second assay uses repair pathway-specific droplet digital PCR assays ('PathSig-dPCR') for absolute quantification of signature DSB repair outcomes. We show that ScarMapper and PathSig-dPCR enable comprehensive assessment of repair pathway utilization in different cell models, after a variety of experimental perturbations. We use these assays to measure the differential impact of DNA end resection on NHEJ, HR and polymerase theta-mediated end joining (TMEJ) repair. These approaches are adaptable to any cellular model system and genomic locus where Cas9-mediated targeting is feasible. Thus, ScarMapper and PathSig-dPCR allow for systematic fate mapping of a targeted DSB with facile and accurate quantification of DSB repair pathway choice at endogenous chromosomal loci.


A Practical Approach to Electrode-Skin Impedance Unbalance Measurement.
Unbalance between electrode-skin impedances is a major problem in biopotential recordings, leading to increased power-line interference. This paper proposes a simple, direct method to measure that unbalance at power-line frequency (50-60Hz), thus allowing the determination of actual recording conditions for biopotential amplifiers. the method is useful in research, amplifier testing, electrode design and teaching purposes. It has been experimentally validated by using both phantom impedances and real electrode-skin impedances.


A novel POLG gene mutation in a patient with SANDO.
The human mitochondrial genome is replicated by DNA polymerase γ, which is encoded by polymerase γ gene (POLG1) on chromosome 15q25. Patients with POLG1 mutations usually present as Alpers' syndrome or progressive external ophthalmoplegia. Our patient was a 48-year old woman with sensory ataxic neuropathy, dysarthria, ophthalmoplegia, and dysphagia. Sequence analysis revealed that she has two heterozygous missense mutations in the POLG1, a c.1774C>T substitution in exon 10, which results in a p.L591F amino acid change; and a c.3286C>T substitution in exon 21, which results in a p.R1096C amino acid change. The 1774C>T substitution is a novel mutation. Previously described adult patients with one mutation in exon 10 and the other in exon 21 of POLG1 had presented with progressive external ophthalmoplegia. We now describe a patient with mutations in the same exons but suffering from the more complex clinical syndrome of sensory ataxic neuropathy, dysarthria, ophthalmoplegia.


Evidence for a possible role of prostaglandins in implantation in rats.
Indomethacin (IM), a potent inhibitor of prostaglandin synthetase, significantly inhibited implantation in rats when administered at a single subcutaneous dose of 15 mg/kg on day 2 or 3 of pregnancy or at a dose of 800 micrograms administered intraluminally in the uterus on day 4 of pregnancy. Indomethacin, administered subcutaneously at a dose of 6 mg/kg on day 3 or 4 of pregnancy and intraluminally at a dose of 800 micrograms/rat on day 4 of pregnancy, also significantly reduced uterine prostaglandin levels. It is suggested that a certain level of uterine prostaglandins is essential for normal implantation and that indomethacin inhibits implantation by reducing uterine prostaglandin levels.


[Migrations forced by violence: the Colombian case].
The human migrations have been one of the motors in the history of humanity. During the twentieth century, internal forced displacement has been an important component of the migration processes in the world. Colombia, a paradigm for this phenomenon, is a country with more than three and a half million people displaced over the last 25 years by force of the violence resulting from an internal armed conflict. Besides the socio-demographic effects in the reconfiguration of the cities, this problem affects the human condition of the victims deteriorating their health and quality of life. This article aims to show the general panorama of migrations forced by violence in the world and to analyze the peculiarities of this phenomenon in the Colombian case. We conclude that forced displacement is a serious violation of human rights producing a human drama by exposing the affected individuals and communities to vulnerability and a deep deterioration of their quality of life and health.


Olfactory responses of Drosophila larvae.
We studied complete dose-response curves for 53 odorants in the third instar larvae of Drosophila melanogaster. All odorants, except one, elicited an attraction response. Some odorants also elicited a decrease from their peak response at higher concentrations. This concentration-dependent decrease in olfactory response could be due to either desensitization or repulsion, 2 possibilities that we cannot distinguish in our current assay. We observed high variations in factors like slopes, thresholds, and peaks of responses that, in agreement with previous studies, suggest that the responses of different receptors are quite different for the similar change in concentration of various ligands. We also observed that lower attraction thresholds predicted higher peak amplitude. This suggests that if odor responses encompassed wider concentration range than can be covered by the dynamic range of a single receptor, then responses tend to be high in magnitude.


[The effects of long-term sedation on intestinal function].
Gastrointestinal integrity with intact function are of main importance in critically ill patients, and not only as a route of nutritional support. Drugs used for long-term sedation can lead to disordered gastrointestinal motility. In this study we compared the influence of different combinations of analgesics and sedatives on the intestinal function in mechanically ventilated, critically ill patients. METHODS. A total of 190 patients were evaluated retrospectively. All patients required controlled mechanical ventilation and deep sedation (Ramsay Score 5-6) for 7 days or more due to acute respiratory failure or elevated intracranial pressure. In none of these patients was enteric tube feeding contraindicated. Intact intestinal function was assumed when full enteric tube feeding was achieved on days 5 and 6 of the treatment period. Furthermore, other gastrointestinal motility disorders (e.g. constipation) had to be absent. In all patients the feeding tube was placed in the stomach by the nasogastric route. Corresponding to different combinations of analgesics and sedatives, the 190 patients were divided into 11 groups. The following combinations were used: group 1 (n = 20), fentanyl+flunitrazepam; group 2 (n = 20), fentanyl+midazolam; group 3 (n = 20), fentanyl+thiopentone; group 4 (n = 20) piritramide+midazolam; group 5 (n = 20), piritramide and continuous epidural administration of bupivacaine+midazolam; group 6 (n = 20), piritramide+gamma-aminobutyric acid (GABA); group 7 (n = 20), ketamine+midazolam; group 8 (n = 10), ketamin+methohexitone; group 9 (n = 20), ketamine+propofol; group 10 (n = 10), ketamine+midazolam and GABA; group 11 (n = 10), sufentail+midazolam and methohexitone. Patients in groups 3, 8, 9, 10, and 11 all had severe head injury and elevated intracranial pressure. Group 6 was made up exclusively of elderly patients (> 65 years) without head trauma. RESULTS. The patients in groups 1, 2, and 3 received fentanyl for analgesia and were completely fed by enteric tube in 30%, 35%, and 15% of cases, respectively. In group 3 deep sedation was necessary because of elevated intracranial pressure. In groups 4, 5, and 6, piritramide was administered for analgesia, and normal enteric tube feeding was achieved in 70%, 75%, and 90% of cases. The best results were seen in group 6, and these elderly patients needed smaller amounts of piritramide for analgesia. In groups 7, 8, 9, and 10, ketamine was given for analgesia, and complete enteric tube feeding was carried out in 75%, 30%, 45%, and 60% of these patients. The best results in the ketamine groups were found in combination with midazolam as the sedating drug; however, the patients in group 7 did not have elevated intracranial pressure, in contrast to the patients in groups 8, 9, and 10. The last group received the combination of sufentanil, midazolam and methohexitone to achieve a deep sedation. The rate of normal enteric tube feeding in these patients with severe head trauma was 30%. CONCLUSIONS. In patients with severe head trauma who need deep sedation to prevent dangerous high intracranial pressure, gastrointestinal motility disorders are very commonly found. The results obtained suggest that ketamine should be regarded as the analgesic drug of choice, combined with propofol rather than a high-dose barbiturate therapy. The combination of ketamine with midazolam and GABA is an unusual strategy for long-term sedation, which resulted from our own clinical studies directed at an effective and well-tolerated regime for this high-risk patient group. Obviously, high-dose barbiturates and short-acting opioids, especially when combined, make enteric tube feeding more difficult. Therefore, we recommend piritramide or ketamine for analgesia. The basic sedating drug is midazolam, in special cases combined with or replaced by propofol. The position of GABA in long-term sedation is not yet clear, but a lack of side effects on the gastrointestinal tract became evident in this stud


Two-layer cold storage method for pancreas and islet cell transplantation.
The two-layer cold storage method (TLM) was first reported in 1988, consisting of a perfluorochemical (PFC) and initially Euro-Collins' solution, which was later replaced by University of Wisconsin solution (UW). PFC is a biologically inert liquid and acts as an oxygen-supplying agent. A pancreas preserved using the TLM is oxygenated through the PFC and substrates are supplied by the UW solution. This allows the pancreas preserved using the TLM to generate adenosine triphosphate during storage, prolonging the preservation time. In a canine model, the TLM was shown to repair and resuscitate warm ischemically damaged pancreata during preservation, improve pancreas graft survival after transplantation, and also improve the islet yield after isolation. Clinical trials using the TLM in pancreas preservation before whole-pancreas transplantation and islet isolation have shown promising outcomes. We describe the role of the TLM in pancreas and islet transplantation.


Toxic effects of various pollutants in 11B7501 lymphoma B cell line from harbour seal (Phoca vitulina).
Although, heavy metals and polycyclic aromatic hydrocarbons (PAHs) have been reported at high levels in marine mammals, little is known about the toxic effects of some of these contaminants. In this study, we assessed the immunotoxic and genotoxic effects of seven heavy metals (arsenic, vanadium, selenium, iron, zinc, silver and chromium) and one PAH (benzo[a]pyrene or B[a]P) on a lymphoma B cell line from harbour seal (Phoca vitulina). A significant reduction in lymphocyte proliferation was registered following an exposure to 0.05 microM of B[a]P, 5 microM of arsenic or selenium, 50 microM of vanadium, 100 microM of silver and 200 microM of iron. On the contrary, zinc increased the lymphoproliferative response at 200 microM. Decreased phagocytosis was observed at 20 microM of arsenic, 50 microM of B[a]P or selenium, 200 microM of zinc and 500 microM of vanadium. Micronuclei induction occurred with 0.2 microM of B[a]P, 100 microM of vanadium and with 200muM of arsenic or selenium. Exposure to 50muM of arsenic decreased G(2)/M phase of the cell cycle. Chromium did not induce any effects at the concentrations tested. Concentrations of heavy metals (except silver and vanadium) and B[a]P inducing an toxic effect are within the environmental ranges reported in the blood tissue of pinnipeds. The reduction of some functional activities of the harbour seal immune system may cause a significant weakness capable of altering host resistance to disease in free-ranging pinnipeds.