Mutagenic analysis of AMP nucleosidase from Escherichia coli. Deletion of a region similar to AMP deaminase and peptide characterization by mass spectrometry.
AMP nucleosidase (EC 184.108.40.206) from Escherichia coli and AMP deaminase (EC 220.127.116.11) from bakers' yeast are proposed to regulate cellular AMP levels under allosteric control of the activator ATP and the inhibitor, PO4. Both enzymes contain catalytic sites which bind AMP and regulatory sites which bind ATP. The deduced amino acid sequences of the proteins revealed only one region of homology in which six of eight amino acids are identical. A similar sequence is found in glyceraldehyde-3-phosphate dehydrogenase, phoE, ras proteins, RNA polymerase, K(+)-ATPase, nucleolin, and other proteins expected to have nucleotide or phosphate binding properties. In the crystal structure of glyceraldehyde-3-phosphate dehydrogenase, this sequence is part of the NAD(+)-binding site. The function of these amino acids was explored with a deletion mutant of AMP nucleosidase. The protein was over-produced in a pTZ construct using the AMP nucleosidase promoter which resulted in approximately 30% of the total protein as the desired enzyme. The mutation was characterized by DNA sequence analysis and by direct analysis of the peptides using high performance liquid chromatography-mass spectrometry. Deletion of amino acids 128-135, corresponding to DGSELTLD, produced an enzyme with a 20-fold decrease in Vmax but with smaller changes in substrate saturation kinetics, activation by MgATP, inhibition by inorganic phosphate, and inhibition by the tight-binding inhibitor, formycin 5-phosphate. The deletion mutant of AMP nucleosidase exhibits hysteresis in establishing a steady-state rate of product formation which is most pronounced in the absence of MgATP. These results establish that the sequence DGSELTLD in E. coli AMP nucleosidase is not required for binding of AMP, MgATP, or inorganic phosphate. However, the mutant enzyme has a structural defect related to the polymerization state which delays the onset of catalysis and decreases the catalytic efficiency.


Decapod crustaceans in fresh waters of southeastern Bahia, Brazil.
A total of 117 species of freshwater decapod crustaceans are known from Brazil. Knowledge regarding the fauna of Decapoda from inland waters in the state of Bahia, northeast Brazil, is incipient. In spite of its wide territory and rich hydrographic net, only 13 species of limnetic decapods have been reported from that state. The objective of this contribution was to survey decapod crustaceans of some hydrographic basins in southeastern Bahia. The material described herein was obtained in samplings conducted between 1997 and 2005. Voucher specimens were deposited in the carcinological collections of the Museu de Zoologia, Universidade Estadual de Santa Cruz, Ilhéus, Brazil, and Departamento de Oceanografia, Universidade Federal de Pernambuco, Recife, Brazil. A total of 13 species was collected. The carideans were represented by the atyids Atya scabra (Leach, 1815) and Potimirim potimirim (Müller, 1881) and the palaemonids Macrobrachium acanthurus (Wiegmann, 1836), M. amazonicum (Heller, 1862), M. carcinus (Linnaeus, 1758), M. heterochirus (Wiegmann, 1836), M. jelskii (Miers, 1877), M. olfersi (Wiegmann, 1836), and Palaemon (Palaemon) pandaliformis (Stimpson, 1871). The brachyurans were represented by the portunids Callinectes bocourti A. Milne-Edwards, 1879 and C. sapidus Rathbun, 1895, the trichodactylid Trichodactylus fluviatilis Latreille, 1828 and the panopeid Panopeus rugosus A. Milne-Edwards, 1881. Macrobrachium heterochirus represents a new record from Bahia, and M. amazonicum is reported for the first time in southeast Bahia. The occurrence of two extreme different forms of T. fluviatilis was observed. Form A is characterized by the frontal margin of carapace bordered by conspicuous granules, the anterolateral margin provided with developed teeth plus granules, and the posterolateral margin provided with granulation similar to that found on the front. In form B the frontal margin is smooth or has an inconspicuous granulation; the anterolateral margin is usually provided with 1-3 notches, and teeth (1-2), if present, are small; and the posterolateral margin is smooth or slightly granulated.


Income inequality and alcohol attributable harm in Australia.
There is little research on the relationship between key socioeconomic variables and alcohol related harms in Australia. The aim of this research was to examine the relationship between income inequality and the rates of alcohol-attributable hospitalisation and death at a local-area level in Australia. We conducted a cross sectional ecological analysis at a Local Government Area (LGA) level of associations between data on alcohol caused harms and income inequality data after adjusting for socioeconomic disadvantage and remoteness of LGAs.The main outcome measures used were matched rate ratios for four measures of alcohol caused harm; acute (primarily related to the short term consequences of drinking) and chronic (primarily related to the long term consequences of drinking) alcohol-attributable hospitalisation and acute and chronic alcohol-attributable death. Matching was undertaken using control conditions (non-alcohol-attributable) at an LGA level. A total of 885 alcohol-attributable deaths and 19467 alcohol-attributable hospitalisations across all LGAs were available for analysis. After weighting by the total number of cases in each LGA, the matched rate ratios of acute and chronic alcohol-attributable hospitalisation and chronic alcohol-attributable death were associated with the squared centred Gini coefficients of LGAs. This relationship was evident after adjusting for socioeconomic disadvantage and remoteness of LGAs. For both measures of hospitalisation the relationship was curvilinear; increases in income inequality were initially associated with declining rates of hospitalisation followed by large increases as the Gini coefficient increased beyond 0.15. The pattern for chronic alcohol-attributable death was similar, but without the initial decrease. There was no association between income inequality and acute alcohol-attributable death, probably due to the relatively small number of these types of death. We found a curvilinear relationship between income inequality and the rates of some types of alcohol-attributable hospitalisation and death at a local area level in Australia. While alcohol-attributable harms generally increased with increasing income inequality, alcohol-attributable hospitalisations actually showed the reverse relationship at low levels of income inequality. The curvilinear patterns we observed are inconsistent with monotonic trends found in previous research making our findings incompatible with previous explanations of the relationship between income inequality and health related harms.


Transcriptional burst fraction and size dynamics during lens fiber cell differentiation and detailed insights into the denucleation process.
Genes are transcribed in irregular pulses of activity termed transcriptional bursts. Cellular differentiation requires coordinated gene expression; however, it is unknown whether the burst fraction (i.e. the number of active phases of transcription) or size/intensity (the number of RNA molecules produced within a burst) changes during cell differentiation. In the ocular lens, the positions of lens fiber cells correlate precisely with their differentiation status, and the most advanced cells degrade their nuclei. Here, we examined the transcriptional parameters of the β-actin and lens differentiation-specific α-, β-, and γ-crystallin genes by RNA fluorescent in situ hybridization (FISH) in the lenses of embryonic day (E) E12.5, E14.5, and E16.5 mouse embryos and newborns. We found that cellular differentiation dramatically alters the burst fraction in synchronized waves across the lens fiber cell compartment with less dramatic changes in burst intensity. Surprisingly, we observed nascent transcription of multiple genes in nuclei just before nuclear destruction. Nuclear condensation was accompanied by transfer of nuclear proteins, including histone and nonhistone proteins, to the cytoplasm. Although lens-specific deletion of the chromatin remodeler SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (Smarca5/Snf2h) interfered with denucleation, persisting nuclei remained transcriptionally competent and exhibited changes in both burst intensity and fraction depending on the gene examined. Our results uncover the mechanisms of nascent transcriptional control during differentiation and chromatin remodeling, confirm the burst fraction as the major factor adjusting gene expression levels, and reveal transcriptional competence of fiber cell nuclei even as they approach disintegration.


Expression of preproenkephalin mRNA by cultured astrocytes and neurons.
Expression of preproenkephalin mRNA by developing glia and neurons was examined in cultures of embryonic and neonatal rat brain. Cultured glia from specific regions of embryonic day 17 and neonatal day 1 rat brain were identified as astrocytes on the basis of both morphology and expression of immunoreactivity for glial fibrillary acidic protein. The level of preproenkephalin mRNA in cultured neonatal hypothalamic astrocytes was comparable to levels present in cultured embryonic striatal and hypothalamic neurons. Levels of the mRNA were significantly higher in astrocytes derived from neonatal hypothalamus compared to astrocytes derived from other areas of the brain. Thus, there is heterogeneity among astrocytes with respect to preproenkephalin expression. Levels of preproenkephalin mRNA in cultured neonatal striatal astrocytes were only one-third as high as levels in embryonic striatal astrocytes; this observation suggests that glial expression of the gene may be down-regulated during development. Although cultured hypothalamic neurons contained substantial levels of prodynorphin mRNA, levels of this mRNA were not detectable in cultured astrocytes from any brain region or in cultured striatal neurons. Thus, glia do not express all opioid peptide genes during development. These observations suggest that expression of the preproenkephalin gene by astrocytes may play a role in development of the brain.


Development of brain mechanisms for visual global processing and object segmentation.
Objects have specific cognitive attributes, elicit particular visuo-motor responses, and require visual processes beyond primary visual cortex to combine information over extended regions as a basis for the segmentation and integration of visual objects. As well as segmentation, the assignment of region boundaries to differentiate figure from ground is a key process whose operation can be observed in infants during the early months. Global organization of both motion and pattern information plays a role in object segmentation and integration. These two types of global processing are associated with different brain systems, have different developmental courses, and are differentially vulnerable in developmental disorders. In infancy, specific visual attributes determine the selection of a manual response (reach-and-grasp vs. surface exploration) and also the detailed kinematic parameters of each class of response. These are taken to reflect the properties of distinct visuo-motor modules whose properties emerge between 4 and 12 months of age. While these modules are a component of the dorsal cortical stream, they must interact with ventral stream processing in development and in the mature system.


Efficacy of repetitive transcranial magnetic stimulation for the treatment of refractory chronic tinnitus: a randomized, placebo controlled study.
The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Low frequency rTMS applied over the auditory cortex has been proposed as a new and causally oriented treatment approach for pathological conditions with abnormal, increased cortical activity including tinnitus with increased activity in the auditory cortex. However available studies are characterized by a positive reports on the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) for treatment of tinnitus, there are few details about the duration of specific treatment effects. The design of the study was randomized, prospective, placebo-controlled. Right-handed patients were treated with either real or sham 1 Hz frequency rTMS over a period of two weeks. Fifty-two patients with chronic, treatment resistant tinnitus and stable medication were enrolled in the study after giving written informed consent and forty-two patients completed the study and were included in data analysis. The ability to reduce the symptoms of tinnitus appeared in both randomized groups immediately after the 1 Hz rTMS and sham stimulation phase. There was a significant reduction in both groups of the tinnitus total score on the Tinnitus Handicap Inventory (THI) (real rTMS p=0.005; sham rTMS p=0.049) and Tinnitus Questionnaire (TQ) total score (real rTMS p=0.003; sham rTMS p=0.049). On the THI evaluation scale, in the real rTMS a mild worsening was noted during week 6 in comparison with the state attained in week 2. During the subsequent course of the study a significant reduction of the total score persisted in the case of THI (real rTMS week 14 p=0.033 and borderline week 26 p=0.058). The reduction of symptoms as evaluated using the TQ was significant compared to baseline in the real rTMS group at week 2, 6 and 14 (p=0.003; p=0.024; p=0.022). The group treated with sham stimulation reached significant reduction of symptoms only at week 2 (p=0.049). A comparison of the difference in the recorded values of the total score during follow-up in relation to baseline expressed as a percentage demonstrates the difference in the effect of rTMS and sham stimulation as evaluated by both the basic scales. Graphical analysis of mean patterns of treatment response according to stimulation type shows a similarity between treatment response patterns evaluated by reduction of the total scores using THI and TQ. The principal finding of this study is that real 1 Hz rTMS treatment was capable of significantly reducing the total baseline score of basic scales that measure tinnitus severity. This result is important as it proves that significant reduction of symptoms can be achieved even in a group of patients with long-term symptoms resistant to pharmacological treatment.


Rupture of the retrocorporeal artery: a rare cause of spontaneous spinal epidural haematoma.
A 22-year-old man presented with a sudden backache and paraplegia (ASIA = B). Magnetic resonance imaging showed an anterior pan-spinal epidural haematoma. Digital subtraction angiography was performed and ruled out an underlying vascular malformation but showed an active contrast media leakage into the T-4 ventral epidural space with a pattern of pseudo-aneurysm. A rupture of a T-4 retrocorporeal artery was considered as the aetiology, possibly caused by a haemorrhagic sub-adventitial dissection. Treatment consisted in the embolisation of both the pseudo-aneurysm and the parent artery with liquid acrylic glue, followed by neurosurgical decompression in emergency. The patient had totally recovered (ASIA = E) by the 10-month clinical follow-up.


Growth inhibition by adenosine 3',5-monophosphate derivatives does not require 3',5' phosphodiester linkage.
Analogs of adenosine 3',5'-monophosphate (cyclic AMP) inhibit the growth of cultured cell lines. The effects of 8-bromo- and N6-butyryl-substituted analogs of cyclic and noncyclic AMP on six cell lines were examined and were equally inhibitory. Variant cell lines with altered cyclic AMP-dependent protein kinase were more resistant to both cyclic and noncyclic nucleotides. We conclude that growth inhibition by analogs of cyclic AMP (i) does not require a 3',5' phosphodiester bond and (ii) may be mediated by a pathway involving endogenous cyclic AMP.


Diet modulates proteinuria in heterozygous female dogs with X-linked hereditary nephropathy.
Young adult heterozygous (carrier) female dogs with X-linked hereditary nephropathy (XLHN) have glomerular proteinuria but are otherwise healthy. Because data regarding dietary influences on the magnitude of proteinuria in dogs with spontaneous glomerular disease are not available, 12 such dogs were studied in a double crossover experiment intended to determine effects of altering dietary protein intake for up to 6 weeks. Dogs were blocked by urine protein : creatinine ratio (UPC) and randomly assigned to receive 2 diets: high protein (34.6% dry matter [DM], HP) or low protein (14.1% DM, LP) fed in HP-LP-HP or LP-HP-LP sequence. Food intake was measured daily, body weight (BW) was measured twice weekly, and UPC, plasma creatinine, blood urea nitrogen, phosphorus, albumin, and protein concentrations were measured at 2-week intervals. Nutrient digestibility was measured during the third treatment period. Diet had a significant effect (P < .0001) on all measured variables except plasma phosphorus (P > .5), but unintended differences in digestibility of protein and energy (P < or = .01) prevented assignment of the diet effect exclusively to protein. Proteinuria was greater (UPC 4.7 +/- 2.2 versus 1.8 +/- 1.1, P < .0001) when the HP diet was fed, but the LP diet did not maintain starting BW or plasma albumin concentration within the normal reference range. Diet greatly affects the magnitude of proteinuria in XLHN carrier females. Dietary protein restriction can reduce proteinuria in dogs with glomerular disease, but BW and blood protein concentrations may not be maintained if the restriction is too severe.


Reliability and validity of cervical auscultation: a controlled comparison using videofluoroscopy.
Cervical auscultation is experiencing a renaissance as an adjunct to the clinical swallowing assessment. It is a controversial technique with a small evidence base. We have aimed to establish whether cervical auscultation interpretation is based on the actual sounds heard or, in practice, influenced by information gleaned from other aspects of the clinical assessment, medical notes, or previous knowledge. We sought to determine (a) rater reliability and its impact on the clinical value of cervical auscultation and (b) how judgments compare with the "gold standard": videofluoroscopy. Swallow sounds were computer recorded via a Littmann stethoscope. Sounds were sampled from 10 healthy control swallows with no aspiration/penetration and 10 patient swallows with aspiration/penetration, all recorded during simultaneous videofluoroscopy. The system generated sound quality similar to "live" bedside listening, a feature rarely seen in cervical auscultation studies. The 20 sound clips were classified as "normal" or "abnormal" by 19 volunteer speech-language pathologists with experience in cervical auscultation. After at least four weeks, 11 of these judges rated the sounds rerandomized on a new CD. Intrarater reliability kappa ranged from -0.12 to 0.71. Individual reliability did not correlate with years of experience, practice pattern, or frequency of use. Interrater reliability kappa = 0.17. Comparison with radiologically defined aspiration/penetration yielded 66% specificity, 62% sensitivity, and majority consensus gave 90% specificity, 80% sensitivity. There was a significant relationship between individual reliability and true positive rate (r(s) = 0.623, p = 0.040). The reliability of individual judges varied widely and thus, inevitably, agreement between judges was poor. Validity is dependent upon reliability: Improving the poor raters would improve the overall accuracy of this technique in predicting abnormality in swallowing. The group consensus correctly identified 17 of the 20 clips so we may speculate that the swallow sound contains audible cues that should in principle permit reliable classification.


Muscarinic receptors and control of airway smooth muscle.
Contraction of airway smooth muscle is mediated by M3 muscarinic receptors on the airway smooth muscle. However, there is no evidence suggesting that hyperresponsiveness results from any alterations in function of these M3 muscarinic receptors. In contrast, there is clearly increased release of the neurotransmitter acetylcholine in animal models of hyperactivity and in asthma. Release of acetylcholine is controlled by inhibitory M2 muscarinic receptors, and it appears that it is these M2 receptors that are dysfunctional in animal models of hyperresponsiveness. Allergen-induced M2 receptor dysfunction is absolutely dependent upon an influx of eosinophils into the airways. Activated eosinophils release major basic protein, which binds to M2 receptors and prevents binding of acetylcholine. Thus, the normal negative feedback control of acetylcholine release is lost, and acetylcholine release is increased. In conclusion, loss of function of inhibitory M2 muscarinic receptors on the airway parasympathetic nerves causes vagally mediated bronchoconstriction and hyperresponsiveness following antigen challenge.


Fundamental immunology and what it can teach us about HIV vaccine development.
This survey covers the immunological background to development of an HIV vaccine, starting from an overview of present understanding of the mechanisms of immunoregulation. It follows the uptake, processing and presentation of an antigen, from its initial uptake by a dendritic cell and its deposit on the dendrites of follicular dendritic cells. It pursues the antigen through uptake by B cells, presentation of epitopes to helper T cells and the eventual production of antibody. In the second arm of the immune response it follows synapse formation between dendritic cell and CD4/CD8 cells leading to production of CTL. It identifies epitope linkage as a key element in directing these pathways. It identifies the principal functions of the various types of cell cooperation. Continuing, it focuses on topics relevant to vaccine development: Th1/Th2 balance: new adjuvants based on ligands of TLRs and other activators of innate immunity, as well as new forms of intervention in antigen processing. We urge that the new vaccine fusion constructs be evaluated against a fusion gold standard rather than against antigen alone. These considerations open new strategies of HIV vaccine development. . Finally we urge that vaccine trials should include storage of individual DNA samples, in order to gain better understanding of the genetic parameters of vaccine efficacy.


The Rx gene confers resistance to a range of potexviruses in transgenic Nicotiana plants.
Rx-mediated resistance was analyzed in Rx-expressing transgenic Nicotiana plants. The infection outcome of nine Potato virus X isolates mutated at amino acid positions 121 and 127 of the coat protein (CP) confirmed the key role of these amino acids but provided a more complex picture than previously reported. In particular, in Rx-expressing Nicotiana spp., eliciting activity modulated by amino acid 121 was conditioned by the nature of amino acid 127. These results suggest that the specificity of recognition might be modulated by host factors that are somehow subtly modified between Rx-expressing potato and Rx-expressing transgenic Nicotiana plants. Moreover, the CP of three Potexviruses, Narcissus mosaic virus (NMV), White clover mosaic virus (WClMV), and Cymbidium mosaic virus (CymMV), are all recognized by the Rx-based machinery and able to trigger an Rx-dependant hypersensitive response. A smaller elicitor of 90 amino acids was identified in the CP of NMV and WClMV, which contains the previously identified key positions 121 and 127. This elicitor is only weakly conserved (approximately 40% identity) among the CP of the various recognized viruses, suggesting that the Rx molecular machinery targets a conserved structural element of the Potexvirus CP rather than a conserved amino acid motif.


Diabetes Caused by Elastase-Cre-Mediated Pdx1 Inactivation in Mice.
Endocrine and exocrine pancreas tissues are both derived from the posterior foregut endoderm, however, the interdependence of these two cell types during their formation is not well understood. In this study, we generated mutant mice, in which the exocrine tissue is hypoplastic, in order to reveal a possible requirement for exocrine pancreas tissue in endocrine development and/or function. Since previous studies showed an indispensable role for Pdx1 in pancreas organogenesis, we used Elastase-Cre-mediated recombination to inactivate Pdx1 in the pancreatic exocrine lineage during embryonic stages. Along with exocrine defects, including impaired acinar cell maturation, the mutant mice exhibited substantial endocrine defects, including disturbed tip/trunk patterning of the developing ductal structure, a reduced number of Ngn3-expressing endocrine precursors, and ultimately fewer β cells. Notably, postnatal expansion of the endocrine cell content was extremely poor, and the mutant mice exhibited impaired glucose homeostasis. These findings suggest the existence of an unknown but essential factor(s) in the adjacent exocrine tissue that regulates proper formation of endocrine precursors and the expansion and function of endocrine tissues during embryonic and postnatal stages.


Angiotensin-converting enzyme genotype affects the response of human skeletal muscle to functional overload.
The response to strength training varies widely between individuals and is considerably influenced by genetic variables, which until now, have remained unidentified. The deletion (D), rather than the insertion (I), variant of the human angiotensin-converting enzyme (ACE) genotype is an important factor in the hypertrophic response of cardiac muscle to exercise and could also be involved in skeletal muscle hypertrophy - an important factor in the response to functional overload. Subjects were 33 healthy male volunteers with no experience of strength training. We examined the effect of ACE genotype upon changes in strength of quadriceps muscles in response to 9 weeks of specific strength training (isometric or dynamic). There was a significant interaction between ACE genotype and isometric training with greater strength gains shown by subjects with the D allele (mean +/- S.E.M.: II, 9.0+/-1.7 %; ID, 17.6 +/-2.2 %; DD, 14.9+/-1.3 %, ANOVA, P 0.05). A consistent genotype and training interaction (ID DD II) was observed across all of the strength measures, and both types of training. ACE genotype is the first genetic factor to be identified in the response of skeletal muscle to strength training. The association of the ACE I/D polymorphism with the responses of cardiac and skeletal muscle to functional overload indicates that they may share a common mechanism. These findings suggest a novel mechanism, involving the renin-angiotensin system, in the response of skeletal muscle to functional overload and may have implications for the management of conditions such as muscle wasting disorders, prolonged bed rest, ageing and rehabilitation, where muscle weakness may limit function.


CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells.
Serum amyloid A (SAA) is a major acute phase protein involved in multiple physiological and pathological processes. This study provides experimental evidence that CD36, a phagocyte class B scavenger receptor, functions as a novel SAA receptor mediating SAA proinflammatory activity. The uptake of Alexa Fluor 488 SAA as well as of other well established CD36 ligands was increased 5-10-fold in HeLa cells stably transfected with CD36 when compared with mock-transfected cells. Unlike other apolipoproteins that bind to CD36, only SAA induced a 10-50-fold increase of interleukin-8 secretion in CD36-overexpressing HEK293 cells when compared with control cells. SAA-mediated effects were thermolabile, inhibitable by anti-SAA antibody, and also neutralized by association with high density lipoprotein but not by association with bovine serum albumin. SAA-induced cell activation was inhibited by a CD36 peptide based on the CD36 hexarelin-binding site but not by a peptide based on the thrombospondin-1-binding site. A pronounced reduction (up to 60-75%) of SAA-induced pro-inflammatory cytokine secretion was observed in cd36(-/-) rat macrophages and Kupffer cells when compared with wild type rat cells. The results of the MAPK phosphorylation assay as well as of the studies with NF-kappaB and MAPK inhibitors revealed that two MAPKs, JNK and to a lesser extent ERK1/2, primarily contribute to elevated cytokine production in CD36-overexpressing HEK293 cells. In macrophages, four signaling pathways involving NF-kappaB and three MAPKs all appeared to contribute to SAA-induced cytokine release. These observations indicate that CD36 is a receptor mediating SAA binding and SAA-induced pro-inflammatory cytokine secretion predominantly through JNK- and ERK1/2-mediated signaling.


Electronic data processing: the pathway to automated quality control of cardiopulmonary bypass.
Electronic data collection during cardiac surgery creates an enormous data source that has many potential applications. After the introduction of the Stockert Data Management System (DMS; Munich, Germany) to our perfusion practice, we recognized that the data could be used for the purpose of quality control (QC). Our aim was to create an automated technique of data analysis and feedback for cardiopulmonary bypass (CPB) procedures. Using visual basic programming, we created a process by which data from the DMS is analyzed and processed in a Microsoft Access database after a CPB procedure. The processing is designed to transfer the collected data to a research database and create a number of CPB quality indicator (QI) parameters, such as mean arterial pressure being less than 40 mmHg for more than 5 minutes or a venous saturation of less than 60% for more than 5 minutes. In the event of QI parameter detection, a QC report is generated and e-mailed to the senior perfusionist and the perfusionist performing the procedure. The introduction of electronic data collection and subsequent development of electronic data processing techniques has enabled us to transfer the data into a readily accessible database and create a data set of perfusion variables and quality indicators for CPB procedures. This data set may be used for immediate automated QC feedback after CPB procedures and direction of performance improvement initiatives through retrospective or prospective data analysis as part of a continuous quality improvement process.


A comparative study of hydrophilic phosphine hexanuclear rhenium cluster complexes' toxicity.
The octahedral rhenium cluster compound Na2H8[{Re6Se8}(P(C2H4CONH2)(C2H4COO)2)6] has recently emerged as a very promising X-ray contrast agent for biomedical applications. However, the synthesis of this compound is rather challenging due to the difficulty in controlling the hydrolysis of the initial P(C2H4CN)3 ligand during the reaction process. Therefore, in this report we compare the in vitro and in vivo toxicity of Na2H8[{Re6Se8}(P(C2H4CONH2)(C2H4COO)2)6] with those of related compounds featuring the fully hydrolysed form of the phosphine ligand, namely Na2H14[{Re6Q8}(P(C2H4COO)3)6] (Q = S or Se). Our results demonstrate that the cytotoxicity and acute in vivo toxicity of the complex Na2H8[{Re6Se8}(P(C2H4CONH2)(C2H4COO)2)6] solutions were considerably lower than those of compounds with the fully hydrolysed ligand P(C2H4COOH)3. Such behavior can be explained by the higher osmolality of Na2H14[{Re6Q8}(P(C2H4COO)3)6] versus Na2H8[{Re6Se8}(P(C2H4CONH2)(C2H4COO)2)6].


Infrared radio-frequency double resonance of (13)CH(3)OH.
Infrared radio-frequency double-resonance spectroscopy has been carried out for (13)CH(3)OH. Four K-type doublet transitions have been observed below 1 GHz, using the 9P(10) and 9P(12) CO(2) laser lines. The results confirm previously proposed assignments of infrared absorption transitions and far-infrared laser emission lines observed in this molecule. Measurements of the A-state splittings have permitted the determination of the asymmetry splitting parameters S(O)(K) and S(CO)(K) for (n, K) = (0, 4) and (1, 3).


Graphene supported non-precious metal-macrocycle catalysts for oxygen reduction reaction in fuel cells.
Fuel cells are promising alternative energy devices owing to their high efficiency and eco-friendliness. While platinum is generally used as a catalyst for the oxygen reduction reaction (ORR) in a typical fuel cell, limited reserves and prohibitively high costs limit its future use. The development of non-precious and durable metal catalysts is being constantly conceived. Graphene has been widely used as a substrate for metal catalysts due to its unique properties, thus improving stability and ORR activities. In this feature, we present an overview on the electrochemical characteristics of graphene supported non-precious metal containing macrocycle catalysts that include metal porphyrin and phthalocyanine derivatives. Suggested research and future development directions are discussed.


Rhinovirus genome evolution during experimental human infection.
Human rhinoviruses (HRVs) evolve rapidly due in part to their error-prone RNA polymerase. Knowledge of the diversity of HRV populations emerging during the course of a natural infection is essential and represents a basis for the design of future potential vaccines and antiviral drugs. To evaluate HRV evolution in humans, nasal wash samples were collected daily for five days from 15 immunocompetent volunteers experimentally infected with a reference stock of HRV-39. In parallel, HeLa-OH cells were inoculated to compare HRV evolution in vitro. Nasal wash in vivo assessed by real-time PCR showed a viral load that peaked at 48-72 h. Ultra-deep sequencing was used to compare the low-frequency mutation populations present in the HRV-39 inoculum in two human subjects and one HeLa-OH supernatant collected 5 days post-infection. The analysis revealed hypervariable mutation locations in VP2, VP3, VP1, 2C and 3C genes and conserved regions in VP4, 2A, 2B, 3A, 3B and 3D genes. These results were confirmed by classical sequencing of additional samples, both from inoculated volunteers and independent cell infections, and suggest that HRV inter-host transmission is not associated with a strong bottleneck effect. A specific analysis of the VP1 capsid gene of 15 human cases confirmed the high mutation incidence in this capsid region, but not in the antiviral drug-binding pocket. We could also estimate a mutation frequency in vivo of 3.4x10(-4) mutations/nucleotides and 3.1x10(-4) over the entire ORF and VP1 gene, respectively. In vivo, HRV generate new variants rapidly during the course of an acute infection due to mutations that accumulate in hot spot regions located at the capsid level, as well as in 2C and 3C genes.


Virtual screening, identification, and biochemical characterization of novel inhibitors of the reverse transcriptase of human immunodeficiency virus type-1.
The reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) is a leading target in current antiretroviral therapy. Unfortunately, drug-resistant RT mutants evolve under the pressure of these drugs, and therefore, new anti-RT inhibitors are constantly required for HIV-1/AIDS treatment. We virtually screened a large chemical library of compounds against two crystal structures of HIV-1 RT to identify novel inhibitors. Top-scoring compounds were tested experimentally; 71 inhibited the RT-associated DNA polymerase, while several also inhibited HIV-1 pseudovirus infection in a cell-based assay. A combination of substituents from two structurally related inhibitors in a single molecule improved the inhibition efficacy. This compound strongly suppressed the RT-associated activity also protecting human lymphocytes from HIV-1 infection. RT inhibition by this compound was reversible and noncompetitive. This molecule and another structurally unrelated potent compound inhibited a known drug-resistant mutant of HIV-1 RT and affected moderately the HIV-2 RT-associated DNA polymerase. These inhibitors may serve as promising anti-HIV lead compounds.


HiTSEE KNIME: a visualization tool for hit selection and analysis in high-throughput screening experiments for the KNIME platform.
We present HiTSEE (High-Throughput Screening Exploration Environment), a visualization tool for the analysis of large chemical screens used to examine biochemical processes. The tool supports the investigation of structure-activity relationships (SAR analysis) and, through a flexible interaction mechanism, the navigation of large chemical spaces. Our approach is based on the projection of one or a few molecules of interest and the expansion around their neighborhood and allows for the exploration of large chemical libraries without the need to create an all encompassing overview of the whole library. We describe the requirements we collected during our collaboration with biologists and chemists, the design rationale behind the tool, and two case studies on different datasets. The described integration (HiTSEE KNIME) into the KNIME platform allows additional flexibility in adopting our approach to a wide range of different biochemical problems and enables other research groups to use HiTSEE.


Studies of the mechanism of action of the Shope rabbit papilloma virus. I. Concerning the nature of the induction of arginase in the infected cells.
These studies make plain that the Shope papilloma virus induces the production of an arginase in rabbit squamous epithelium, and provide evidence that the information for the synthesis of the enzyme is derived from the virus rather than the rabbit. This form of induction is therefore different from that brought about by chemicals such as galactosides (36). Striking differences were shown between the physiochemical properties of Shope virus-induced arginase and other arginases of domestic and Kansas cottontail rabbits. The absence of a requirement for manganese suggests the mechanism of splitting off urea from arginine by papilloma arginase probably differs from that of previously described arginases. These findings (particularly the experiments in which it was demonstrated that papilloma growth could be greatly reduced by giving animals supplemental arginine in the presence of small amounts of the arginase inhibitor, canavanine) provide evidence that suggests the following mechanism of action for the virus: viral DNA introduces into rabbit epithelium the information for the synthesis of an arginase for which the cells have no control mechanism. The arginase depletes cellular arginine and, in turn, the synthesis of arginine-rich nuclear histones (2), thereby freeing the nucleus for greater synthetic activity (4, 35), which results in more rapid growth of the papilloma cells. Domestic rabbit papillomas induced with purified virus derived from wild rabbit papillomas were shown to contain an antigen which reacts immunologically like a wild rabbit antigen. It was distinct from the arginase, the protein coat of the virus, and the Vx-2 antigen. The presence of the wild rabbit antigen seems indicative of integration of the virus DNA in the host genome of the wild rabbit. Other incidental findings include the description of a simple method, accurate to within 1 per cent, for determining the partial specific volume of a protein, and the description of a modification of the Richards and Schachman method (9) enabling the determination of the molecular weight and homogeneity of a protein with as little as 0.25 mg and with an accuracy of 2 per cent.


Prediction of rapid amyloid and phosphorylated‐Tau accumulation in cognitively healthy individuals.
To test the hypothesis that among cognitively healthy individuals, distinct groups exist in terms of amyloid and phosphorylated-tau accumulation rates; that if rapid accumulator groups exist, their membership can be predicted by Alzheimer's disease (AD) risk factors, and that time points of significant increase in AD protein accumulation will be evident. The analysis reports data from 263 individuals from the BIOCARD and 184 individuals from the Baltimore Longitudinal Study of Aging with repeated cerebrospinal fluid (CSF) and positron emission tomography (PET) sampling, respectively. We used latent class mixed-effect models to identify distinct classes of amyloid (CSF and PET) and p-Tau (CSF) accumulation rates and generalized additive modeling to investigate non-linear changes to AD biomarkers. For both amyloid and p-Tau latent class models we confirmed the existence of two separate classes: accumulators and non-accumulators. The accumulator and non-accumulator groups differed significantly in terms of baseline AD protein levels and slope of change. APOE ε4 carrier status and episodic memory predicted amyloid class membership. Non-linear models revealed time points of significant increase in the rate of amyloid and p-Tau accumulation whereby APOE ε4 carrier status associated with earlier age at onset of rapid accumulation. The current analysis demonstrates the existence of distinct classes of amyloid and p-Tau accumulators. Predictors of class membership were identified but the overall accuracy of the models was modest, highlighting the need for additional biomarkers that are sensitive to early disease phenotypes.


Deterministic generation of an on-demand Fock state.
We theoretically study the deterministic generation of photon Fock states on-demand using a protocol based on a Jaynes Cummings quantum random walk which includes damping. We then show how each of the steps of this protocol can be implemented in a low temperature solid-state quantum system with a Nitrogen-Vacancy centre in a nanodiamond coupled to a nearby high-Q optical cavity. By controlling the coupling duration between the NV and the cavity via the application of a time dependent Stark shift, and by increasing the decay rate of the NV via stimulated emission depletion (STED) a Fock state with high photon number can be generated on-demand. Our setup can be integrated on a chip and can be accurately controlled.


The prevalence of a YY synaptonemal complex over XY synapsis in an XYY man with exclusive XYY spermatocytes.
An infertile XYY man was studied by synaptonemal complex analysis of microspread spermatocytes and by quantitation of germ cells in semithin sections. All the 74 spermatocytes micrographed have an XYY constitution, and the biopsy shows a homogeneous arrest of spermatogenesis at the spermatocyte/young spermatid stages. The overwhelming majority (86%) of spermatocytes showed a Y-Y bivalent plus a univalent X. The Y-Y bivalent is totally synapsed in 48% of the cells. In the remaining cells, the YY bivalent has an average synaptic segment covering 43% of its length that always includes Yp. Another 9% of the spermatocytes showed an XYY trivalent and 4% of the spermatocytes showed univalence of the three gonosomes. Progression through all the pachytene substages was observed in cells with the two main synaptic configurations, but a high level of germ cell death was observed at or immediately after the meiotic divisions. The prevalence of Y-Y synapsis arises from the longer homologous region and the higher speed of pairing between the two Y chromosomes. Germ cell death is probably related to the univalence of the X chromosome. Synaptic competition between three gonosomes seems to be similar to that found in triploid birds but is somewhat different from that of XYY mice.


Situational and psycho-social factors associated with relapse following residential detoxification in a population of Irish opioid dependent patients.
To identify and describe the context and factors involved in the opioid lapse process following discharge from an Irish inpatient opioid detoxification treatment programme. Design, participants, setting: Prospective follow-up study of consecutive detoxified opioid dependent patients treated in a specialist inpatient drug dependency unit. The Maudsley Addiction Profile and a structured interview were administered to 109 patients, 18-36 months after discharge. Of 109 people interviewed at follow-up, 102 (94%) reported at least one episode of opioid use after leaving the residential treatment programme. Eighty eight patients (86% of the lapsers) identified more than one major factor contributing to their recidivism. The median number of factors identified as having a major role in the lapse was four. The most frequently reported major contributors to lapse were low mood (62%), difficulties with craving (62%), ease of access to heroin (48%) and missing the support of the treatment centre (43%). Early lapse was common following inpatient treatment of opioid dependence. Lapse tended to result from a number of common, identifiable, high-risk situations, feelings and cognitions which may assist clinicians and patients develop lapse prevention strategies to anticipate and interrupt this process.


Different binding modes of free and carrier-protein-coupled nicotine in a human monoclonal antibody.
Nicotine is the principal addictive component of tobacco. Blocking its passage from the lung to the brain with nicotine-specific antibodies is a promising approach for the treatment of smoking addiction. We have determined the crystal structure of nicotine bound to the Fab fragment of a fully human monoclonal antibody (mAb) at 1.85 Å resolution. Nicotine is almost completely (>99%) buried in the interface between the variable domains of heavy and light chains. The high affinity of the mAb is the result of a charge-charge interaction, a hydrogen bond, and several hydrophobic contacts. Additionally, similarly to nicotinic acetylcholine receptors in the brain, two cation-π interactions are present between the pyrrolidine charge and nearby aromatic side chains. The selectivity of the mAb for nicotine versus cotinine, which is the major metabolite of nicotine and differs in only one oxygen atom, is caused by steric constraints in the binding site. The mAb was isolated from B cells of an individual immunized with a nicotine-carrier protein conjugate vaccine. Surprisingly, the nicotine was bound to the Fab fragment in an orientation that was not compatible with binding to the nicotine-carrier protein conjugate. The structure of the Fab fragment in complex with the nicotine-linker derivative that was used for the production of the conjugate vaccine revealed a similar position of the pyridine ring of the nicotine moiety, but the pyrrolidine ring was rotated by about 180°. This allowed the linker part to reach to the Fab surface while high-affinity interactions with the nicotine moiety were maintained.


Relationship of orthopedic examination, goniometric measurements, and radiographic signs of degenerative joint disease in cats.
Available information suggests a mismatch between radiographic and orthopedic examination findings in cats with DJD. However, the extent of the discrepancy between clinical and radiographic signs of OA in companion animals has not been described in detail. This study aimed to evaluate the relationship between orthopedic examination findings, joint goniometry, and radiographic signs of DJD in 100 cats, in a prospective observational design. Cat temperament, pain response to palpation, joint crepitus, effusion and thickening were graded. Radiographs of appendicular joints and the axial skeleton were made under sedation. Joint motion was measured by use of a plastic goniometer before and after sedation. Associations between radiographic degenerative joint disease (DJD) and examination findings were assessed to determine sensitivity, specificity and likelihood estimations. Pain response to palpation was elicited in 0-67% of the joints with DJD, with a specificity ranging from 62-99%; crepitus was detected in 0-56% of the joints and its specificity varied between 87 and 99%; for effusion, values ranged between 6 and 38% (specificity, 82-100%), and thickening, 0-59% (specificity, 74-99%). Joints with DJD tended to have a decreased range of motion. The presence of pain increased the odds of having DJD in the elbow (right: 5.5; left: 4.5); the presence of pain in the lower back increased the odds of spinal DJD being present (2.97 for lumbar; 4.67 for lumbo-sacral). Radiographic DJD cannot be diagnosed with certainty using palpation or goniometry. However, negative findings tend to predict radiographically normal joints. Palpation and goniometry may be used as a tool to help to screen cats, mostly to rule out DJD.


Does animal behavior underlie covariation between hosts' exposure to infectious agents and susceptibility to infection? Implications for disease dynamics.
Animal behavior is unique in influencing both components of the process of transmission of disease: exposure to infectious agents, and susceptibility to infection once exposed. To date, the influence of behavior on exposure versus susceptibility has largely been considered separately. Here, we ask whether these two key mechanisms act in concert in natural populations, whereby individuals who are most exposed to infectious agents or have the most contact with conspecifics are also the most susceptible or infectious. We propose three mechanisms that can generate covariation between these two key elements of the transmission of disease within and among hosts, and we provide empirical examples of each. We then use a mathematical model to examine the effect of this covariation on the dynamics of disease at the population level. First, we show that the empirical mechanisms generating covariation between behavioral and physiological components of disease transmission are widespread and include endocrine mediators of behavior, mate choice, group size, sickness behaviors, and behavioral avoidance of infectious conspecifics. The diversity of these empirical mechanisms underscores the potential importance and breadth of covariation in the disease process. Second, we show mathematically that the variability in hosts' exposure to infectious agents and susceptibility or infectiousness, and how tightly they are coupled, strongly influences the ability of a disease to invade a host population. Overall, we propose that covariation between behavioral and physiological components of transmission is likely widespread in natural populations, and can have important consequences for the dynamics of disease at the population level as well as for our understanding of sexual selection, social behavior, and animal communication.


Survivorship: screening for cancer and treatment effects, version 2.2014.
The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common physical and psychosocial consequences of cancer and cancer treatment. This portion of the guidelines describes recommendations regarding screening for the effects of cancer and its treatment. The panel created a sample screening tool, specifically for use in combination with the NCCN Guidelines for Survivorship, to guide providers to topics that require more in-depth assessment. Effective screening and assessment can help providers deliver necessary and comprehensive survivorship care.


High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women.
1. A randomized, double-blind, placebo-controlled trial utilizing creatine as a potential lipid-lowering agent was conducted to determine plasma lipid, lipoprotein, glucose, urea nitrogen and creatinine profiles in men and women ranging in age from 32 to 70 years. 2. Thirty-four subjects (18 men and 16 women) with total cholesterol concentrations exceeding 200 mg/dl received either a creatine supplement (5 g of creatine plus 1 g of glucose) or a glucose placebo (6 g of glucose) for 56 days. Creatine and placebo were taken orally four times a day for 5 days and then twice a day for 51 days. Plasma analyses were measured at baseline, 4 and 8 weeks of treatment, and at 4 weeks after cessation of treatment (week 12). 3. Significant reductions in plasma total cholesterol, triacylglycerols and very-low-density lipoprotein-C occurred within the creatine monohydrate group. Minor reductions in plasma total cholesterol from baseline (233 +/- 9 mg/dl) of 6% and 5% occurred at weeks 4 and 8, respectively, before returning to baseline at week 12. Baseline triacylglycerols (194 +/- 21 mg/dl) and very-low-density lipoprotein-C (39 +/- 4 mg/dl) were reduced by 23% and 22% at weeks 4 and 8, respectively, and remained attenuated by 26% at week 12. These results remained consistent when data were separated and analysed by gender. Finally, a small, but statistically significant increase in urea nitrogen was observed in women between baseline (11.8 +/- 0.7 mg/dl) and week 8 (13.8 +/- 0.7 mg/dl, P < 0.05). No significant differences were noted for low-density lipoprotein-C, high-density lipoprotein-C, total cholesterol/high-density lipoprotein ratio, glucose, creatinine, body mass, body mass index or physical activity within or between the experimental and placebo groups. However, a trend towards reduced blood glucose levels was present in males given creatine monohydrate (P = 0.051). 4. These preliminary data suggest that creatine monohydrate may modulate lipid metabolism in certain individuals. These observations may demonstrate practical efficacy to the hyperlipidaemic patient as well as providing possible new mechanistic insights into the cellular regulation of blood lipid concentrations.


Paper-marking test for chimpanzee: simple control for social cues.
A series of paper-marking tests, modeled after tests widely applied to humans, was administered to Sarah, a "language"-trained chimpanzee (Pan troglodytes). The test format was simple, economical, and controlled for social cues. The ape successfully made same-similar-different judgments on pictures of familiar objects when up to four questions were presented at the same time. Performance remained satisfactory on same-different judgments of novel pictures of alphabetic characters. Throughout the series of tests, the subject showed a superiority on same judgments.


Intensive insulin therapy for acute hyperglycemia.
There is growing evidence that control of hyperglycemia in the critically ill patient improves outcome. Normalizing blood glucose levels decreases the risk of developing sepsis, end-organ damage, and hospital mortality. Critical care clinicians must be familiar with current and benchmark research supporting control of hyperglycemia and use this knowledge to ensure appropriate application of evidence-based practice for decreasing or preventing complications in the critically ill patient. This article describes the effects of hyperglycemia and discusses the evidence supporting tight glycemic control in such patients. The necessary steps to implement an intensive insulin therapy protocol for control of acute hyperglycemia are detailed.


An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII.
EGFRvIII is a key oncogene in glioblastoma (GBM). EGFRvIII results from an in-frame deletion in the extracellular domain of EGFR, does not bind ligand and is thought to be constitutively active. Although EGFRvIII dimerization is known to activate EGFRvIII, the factors that drive EGFRvIII dimerization and activation are not well understood. Here we present a new model of EGFRvIII activation and propose that oncogenic activation of EGFRvIII in glioma cells is driven by co-expressed activated EGFR wild type (EGFRwt). Increasing EGFRwt leads to a striking increase in EGFRvIII tyrosine phosphorylation and activation while silencing EGFRwt inhibits EGFRvIII activation. Both the dimerization arm and the kinase activity of EGFRwt are required for EGFRvIII activation. EGFRwt activates EGFRvIII by facilitating EGFRvIII dimerization. We have previously identified HB-EGF, a ligand for EGFRwt, as a gene induced specifically by EGFRvIII. In this study, we show that HB-EGF is induced by EGFRvIII only when EGFRwt is present. Remarkably, altering HB-EGF recapitulates the effect of EGFRwt on EGFRvIII activation. Thus, increasing HB-EGF leads to a striking increase in EGFRvIII tyrosine phosphorylation while silencing HB-EGF attenuates EGFRvIII phosphorylation, suggesting that an EGFRvIII-HB-EGF-EGFRwt feed-forward loop regulates EGFRvIII activation. Silencing EGFRwt or HB-EGF leads to a striking inhibition of EGFRvIII-induced tumorigenicity, while increasing EGFRwt or HB-EGF levels resulted in accelerated EGFRvIII-mediated oncogenicity in an orthotopic mouse model. Furthermore, we demonstrate the existence of this loop in human GBM. Thus, our data demonstrate that oncogenic activation of EGFRvIII in GBM is likely maintained by a continuous EGFRwt-EGFRvIII-HB-EGF loop, potentially an attractive target for therapeutic intervention.


Predicting childhood effortful control from interactions between early parenting quality and children's dopamine transporter gene haplotypes.
Children's observed effortful control (EC) at 30, 42, and 54 months (n = 145) was predicted from the interaction between mothers' observed parenting with their 30-month-olds and three variants of the solute carrier family C6, member 3 (SLC6A3) dopamine transporter gene (single nucleotide polymorphisms in intron8 and intron13, and a 40 base pair variable number tandem repeat [VNTR] in the 3'-untranslated region [UTR]), as well as haplotypes of these variants. Significant moderating effects were found. Children without the intron8-A/intron13-G, intron8-A/3'-UTR VNTR-10, or intron13-G/3'-UTR VNTR-10 haplotypes (i.e., haplotypes associated with the reduced SLC6A3 gene expression and thus lower dopamine functioning) appeared to demonstrate altered levels of EC as a function of maternal parenting quality, whereas children with these haplotypes demonstrated a similar EC level regardless of the parenting quality. Children with these haplotypes demonstrated a trade-off, such that they showed higher EC, relative to their counterparts without these haplotypes, when exposed to less supportive maternal parenting. The findings revealed a diathesis-stress pattern and suggested that different SLC6A3 haplotypes, but not single variants, might represent different levels of young children's sensitivity/responsivity to early parenting.


An Analysis of 2.3 Million Participations in the Continuing Medical Education Program of a General Medical Journal: Suitability, User Characteristics, and Evaluation by Readers.
Physicians frequently use continuing medical education (CME) in journals. However, little is known of the evaluation of journal CME by readers and also user and participation characteristics. Deutsches Ärzteblatt, the journal of the German Medical Association, is distributed to every physician in Germany and regularly offers its readers CME articles. Therefore, it provides a unique opportunity to analyze a journal CME program directed at an entire population of physicians. The aim is to show key sociodemographic characteristics of participants, frequency and temporal distributions of participations, and to analyze whether the articles are suitable for a general medical audience, how physicians rate the CME articles, how successful they were in answering simple multiple-choice questions, and to detect distinct clusters of participants. Using obligatory online evaluation forms and multiple-choice questions, we analyzed all participations of the entire 142 CME articles published between September 2004 and February 2014. We compared demographic characteristics of participants with official figures on those characteristics as provided by the German Medical Association. A total of 128,398 physicians and therapists (male: 54.64%, 70,155/128,393; median age class 40 to 49 years) participated 2,339,802 times (mean 16,478, SD 6436 participations/article). Depending on the year, between 12.33% (44,064/357,252) and 16.15% (50,259/311,230) of all physicians in the country participated at least once. The CME program was disproportionally popular with physicians in private practice, and many participations took place in the early mornings and evenings (4544.53%, 1,041,931/2,339,802) as well as over the weekend (28.70%, 671,563/2,339,802). Participation by specialty (ranked in descending order) was internal medicine (18.25%, 23,434/128,392), general medicine (16.38%, 21,033/128,392), anesthesiology (10.00%, 12,840/128,392), and surgery (7.06%, 9059/128,392). Participants rated the CME articles as intelligible to a wider medical audience and filling clinically relevant knowledge gaps; 78.57% (1,838,358/2,339,781) of the sample gave the CME articles very good or good marks. Cluster analysis revealed three groups, one comprised of only women, with two-thirds working in private practice. The CME article series of Deutsches Ärzteblatt is used on a regular basis by a considerable proportion of all physicians in Germany; its multidisciplinary articles are suitable to a broad spectrum of medical specialties. The program seems to be particularly attractive for physicians in private practice and those who want to participate from their homes and on weekends. Although many physicians emphasize that the articles address gaps in knowledge, it remains to be investigated how this impacts professional performance and patient outcomes.


Improvement of digital photoelasticity based on camera response function.
Studies on photoelasticity have been conducted by many researchers in recent years, and many equations for photoelastic analysis based on digital images were proposed. While these equations were all presented by the light intensity emitted from the analyzer, pixel values of the digital image were actually used in the real calculations. In this paper, a proposal of using relative light intensity obtained by the camera response function to replace the pixel value for photoelastic analysis was investigated. Generation of isochromatic images based on relative light intensity and pixel value were compared to evaluate the effectiveness of the new approach. The results showed that when relative light intensity was used, the quality of an isochromatic image can be greatly improved both visually and quantitatively. We believe that the technique proposed in this paper can also be used to improve the performance for the other types of photoelastic analysis using digital images.


Quantifying Long-Range Interactions and Coherent Structure in Multi-Agent Dynamics.
We develop and apply several novel methods quantifying dynamic multi-agent team interactions. These interactions are detected information-theoretically and captured in two ways: via (i) directed networks (interaction diagrams) representing significant coupled dynamics between pairs of agents, and (ii) state-space plots (coherence diagrams) showing coherent structures in Shannon information dynamics. This model-free analysis relates, on the one hand, the information transfer to responsiveness of the agents and the team, and, on the other hand, the information storage within the team to the team's rigidity and lack of tactical flexibility. The resultant interaction and coherence diagrams reveal implicit interactions, across teams, that may be spatially long-range. The analysis was verified with a statistically significant number of experiments (using simulated football games, produced during RoboCup 2D Simulation League matches), identifying the zones of the most intense competition, the extent and types of interactions, and the correlation between the strength of specific interactions and the results of the matches.


Healthcare Professional Preferences for Prescribing Artemisinins and Quinine for Malaria in Burundi.
Malaria is a significant cause of morbidity and mortality throughout the world and particularly sub-Saharan Africa. The World Health Organization and many national bodies, including Burundi, recommend artemisinin-based therapy as first-line treatment for uncomplicated and severe malaria. Implementing this recommendation requires healthcare professionals' acceptance of this treatment as the optimal choice. A survey was conducted among Burundian healthcare professionals from June to September 2017 to assess prescribing preferences regarding artemisinins versus quinine for treating malaria. Healthcare professionals were surveyed from 32 health facilities in 10 provinces. Respondents included both physicians and nurses who provided responses about their antimalarial treatment preferences for a variety of clinical scenarios. Comparisons among healthcare professionals, their level of training, work setting, and length of work experience were examined using a series of stratified analyses, where the Pearson Chi-square statistic and odds ratios with 95% confidence intervals were calculated. Respondents included 101 doctors and 196 nurses. Seventy-nine percent of respondents worked in hospitals, while 58% had more than 5 years of work experience. Although 94% of respondents correctly identified artemisinin-based treatment as first-line therapy according to the national protocol, 24-40% of respondents preferred the use of quinine in various hypothetical clinical scenarios. Overall, nurses were at greater odds of preferring quinine versus artemisinins compared with physicians. Availability of artemisinins was associated positively with artemisinin preference. These results did not vary by duration of work experience. Though knowledge of artemisinin-based therapy was recognised by the majority of respondents as the recommended antimalarial treatment, a high proportion of Burundian healthcare professionals, especially nurses, prefer using oral and IV quinine in a number of clinical scenarios. These findings identify a significant barrier to the satisfactory implementation of a life-saving treatment in accordance with national and international recommendations.


Impact of resolution and noise characteristics of digital radiographic detectors on the detectability of lung nodules.
One of the unanswered questions in digital radiography is the connection between physical image quality metrics and clinical detection performance. In this paper, we examine the impact of two physical metrics, resolution and noise, on the detectability of nodules in a pulmonary background for specific digital radiographic detectors. A detection experiment was performed on a simulated image set using anatomical backgrounds from a high-quality lung radiograph and three different simulated nodule sizes (2-3.5 mm). The resolution and noise of the resulting images were modified using existing routines to simulate a selenium-based and a cesium iodide-based flat-panel detector at comparable exposures. A location-known-exactly (LKE) observer performance experiment was performed in which four experienced chest radiologists and three physicists specializing in chest radiology scored the images. The data from the observer experiment were analyzed by receiver operating characteristic (ROC) methodology. The detectability, as measured by the parameter Az, was higher for the selenium detector than the cesium iodide detector for all nodule sizes by an average of 8.5%. For one nodule size (2.75 mm), the difference between detectors was statistically significant (p < 0.01). The findings indicate that for the particular task studied, the superior resolution performance of the selenium-based detector provided better detectability of subtle lung nodules even though the images had greater noise than images obtained with the cesium iodide detector.


Regioselective preparation of benzo[b]furans from phenols and α-bromoketones.
In this paper, a fully regiocontrolled synthesis of either 2- and 3-substituted benzo[b]furans is described. Direct reaction between phenols and α-bromoacetophenones in the presence of neutral alumina yields 2-substituted benzo[b]furans with complete regiocontrol. When a basic salt such as potassium carbonate is used, the corresponding 2-oxoether is obtained. Cyclization of these latter compounds promoted by neutral alumina yields the corresponding 3-substituted benzo[b]furans. Using the former method, Moracin M and other analogues can be obtained from commercial sources in two preparative steps. DFT calculations provide reasonable reaction paths to understand the formation of 2-substituted benzo[b]furans.


Optical ptychography: a practical implementation with useful resolution.
Quantitative phase microscopy offers a range of benefits over conventional phase-contrast techniques. For example, changes in refractive index and specimen thickness can be extrapolated and images can be refocused subsequent to their recording. In this Letter, we detail a lensless, quantitative phase microscope with a wide field of view and a useful resolution. The microscope uses the recently reported coherent diffractive imaging technique of ptychography to generate images from recorded diffraction patterns.


The strength and timing of the mitochondrial bottleneck in salmon suggests a conserved mechanism in vertebrates.
In most species mitochondrial DNA (mtDNA) is inherited maternally in an apparently clonal fashion, although how this is achieved remains uncertain. Population genetic studies show not only that individuals can harbor more than one type of mtDNA (heteroplasmy) but that heteroplasmy is common and widespread across a diversity of taxa. Females harboring a mixture of mtDNAs may transmit varying proportions of each mtDNA type (haplotype) to their offspring. However, mtDNA variants are also observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte, which suggests a genetic bottleneck acts during mtDNA transmission. Understanding the size and timing of this bottleneck is important for interpreting population genetic relationships and for predicting the inheritance of mtDNA based disease, but despite its importance the underlying mechanisms remain unclear. Empirical studies, restricted to mice, have shown that the mtDNA bottleneck could act either at embryogenesis, oogenesis or both. To investigate whether the size and timing of the mitochondrial bottleneck is conserved between distant vertebrates, we measured the genetic variance in mtDNA heteroplasmy at three developmental stages (female, ova and fry) in chinook salmon and applied a new mathematical model to estimate the number of segregating units (N(e)) of the mitochondrial bottleneck between each stage. Using these data we estimate values for mtDNA Ne of 88.3 for oogenesis, and 80.3 for embryogenesis. Our results confirm the presence of a mitochondrial bottleneck in fish, and show that segregation of mtDNA variation is effectively complete by the end of oogenesis. Considering the extensive differences in reproductive physiology between fish and mammals, our results suggest the mechanism underlying the mtDNA bottleneck is conserved in these distant vertebrates both in terms of it magnitude and timing. This finding may lead to improvements in our understanding of mitochondrial disorders and population interpretations using mtDNA data.


Exchange Often and Properly in Replica Exchange Molecular Dynamics.
Previous work by us showed that in replica exchange molecular dynamics, exchanges should be attempted extremely often, providing gains in efficiency and no undesired effects. Since that time some questions have been raised about the extendability of these claims to the general case. In this work, we answer this question in two ways. First, we perform a study measuring the effect of exchange attempt frequency in explicit solvent simulations including thousands of atoms. This shows, consistent with the previous assertion, that high exchange attempt frequency allows an optimal rate of exploration of configurational space. Second, we present an explanation of many theoretical and technical pitfalls when implementing replica exchange that cause "improper" exchanges resulting in erroneous data, exacerbated by high exchange attempt frequency.


In vitro fermentation of chewed mango and banana: particle size, starch and vascular fibre effects.
Fruits (and vegetables) contain cellular structures that are not degraded by human digestive enzymes. Therefore, the structure of the insoluble fraction of swallowed fruits is mostly retained until intestinal microbial fermentation. In vitro fermentation of mango and banana cell structures, which survived in vivo mastication and in vitro gastrointestinal digestion, were incubated with porcine faecal inoculum and showed intensive metabolic activity. This included degradation of cell walls, leading to the release of encapsulated cell contents for further microbial metabolism. Production of cumulative gas, short chain fatty acids and ammonia were greater for mango than for banana. Microscopic and spectroscopic analyses showed this was due to a major fermentation-resistant starch fraction present in banana, that was absent in mango. This study demonstrated distinctive differences in the fermentability of banana and mango, reflecting a preferential degradation of (parenchyma) fleshy cell walls over resistant starch in banana, and the thick cellulosic vascular fibres in mango.


Healthy Aging Brain Center improved care coordination and produced net savings.
Over the past two decades the collaborative care model within primary care has proved to be effective in improving care quality, efficiency, and outcomes for older adults suffering from dementia and depression. In collaboration with community partners, scientists from Indiana University have implemented this model at the Healthy Aging Brain Center (HABC), a memory care clinic that is part of Eskenazi Health, an integrated safety-net health care system in Indianapolis, Indiana. The HABC generates an annual net cost savings of up to $2,856 per patient, which adds up to millions of dollars for Eskenazi Health's patients. This article demonstrates the financial sustainability of the care processes implemented in the HABC, as well as the possibility that payers and providers could share savings from the use of the HABC model. If it were implemented nationwide, annual cost savings could be in the billions of dollars.


Education, marital status, and risk of hip fractures in older men and women: the CHANCES project.
The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk. The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA. A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models. Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P heterogeneity > 0.05). The combined data from >150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting.


Treatment of oblique crown fractures in maxillary premolars using adhesive tooth fragment reattachment: 19 years of follow up.
This report presents an oblique crown fracture in the maxillary right premolars of an adolescent because of fall, which was treated using adhesive tooth fragment reattachment. The impact of the mandible base to the floor caused minor fractures in multiple teeth, severe fracture of teeth 14 and 15, and condylar fractures. The fragments of teeth 43, 45, 46, and 16 were lost at the site of accident. The condylar fractures were managed with a non-surgical conservative approach combining mandibular immobilization and stabilization of temporomandibular joints with maxillomandibular fixation using acrylic splints. After 3 months, the interocclusal splints were removed, and the patient was referred for dental care. Teeth 14 and 15 presented complicated oblique crown fractures causing separation of the buccal and palatal fragments, which were in place, attached to the gingival tissue. Tooth 15 presented chronic hyperplastic pulpits. The fragments were banded for stabilization during the endodontic treatment, and the bands served as matrix for adhesive tooth fragment reattachment. The other fractured teeth received direct composite resin restorations. After 8 years, tooth 16 developed pulp necrosis and was treated endodontically and restored with composite resin. Clinical and radiographic examination 19 years after trauma showed a good adaptation of the tooth fragment/composite resin restoration, good periodontal health, no signs of root resorption, and intact lamina dura.


Altered serotonin, dopamine and norepinepherine levels in 15q duplication and Angelman syndrome mouse models.
Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain.


Quantifying noxious-evoked baseline sensitivity in neonates to optimise analgesic trials.
Despite the high burden of pain experienced by hospitalised neonates, there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG (electroencephalography)-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy; however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here, we present an experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental, and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.


Hypertension in pediatric patients on long-term dialysis: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).
Elevated blood pressure (BP) is frequent in children on long-term dialysis therapy. However, the prevalence of hypertension and status of BP control in these patients are lacking. Using the North American Pediatric Renal Transplantation Cooperative Study database, we determined the prevalence of hypertension and assessed risk factors for elevated BP during long-term dialysis therapy in children. The study cohort included 3,743 patients (age, 0 to 21 years). Uncontrolled hypertension is defined as BP equal to or greater than age-, sex-, and height-specific 95th percentiles; controlled hypertension was considered in children who were administered antihypertensive medications, but had BP less than the 95th percentile. A total of 76.6% of patients had either uncontrolled (56.9%) or controlled (19.7%) hypertension at baseline. Normotensive children at baseline had significant BP increases, whereas hypertensive children at baseline had significant BP decreases during the first year of dialysis therapy. BP did not change significantly after 1 year of dialysis therapy; 51% of patients had uncontrolled hypertension after 1 year of maintenance dialysis therapy. Logistic regression analysis shows that baseline hypertensive status and use of BP medications are both large significant risk factors for subsequent hypertension. Other risk factors include young age, acquired cause of renal failure, black race, initiation of dialysis therapy in 1992 to 1997, and hemodialysis as a mode of renal replacement therapy. Hypertension is very prevalent and difficult to control in children on dialysis therapy. Results also suggest that the initial months on maintenance dialysis therapy might be the window of opportunity when careful monitoring and aggressive management of hypertension would allow achieving BP control in these patients.


Design and performance of a programmable spatial CCD filter.
Parallel signal preprocessing techniques in an image plane, as suggested by the mechanism of human vision, are used to improve the performance of a solid-state imaging sensor. In this paper a 3 x 3 neighborhood operator, by which the gray level of a particular pixel in a transformed image can be determined from the gray levels of the corresponding pixel and its neighborhood in the original image by using appropriate algorithms, is discussed. Dynamic trade-off of signal-to-noise ratio for resolution depending on the light level is realized by combining a newly designed CCD spatial filter with variable weighting circuitry. Improvement in sensitivity by as much as 11 dB at low light levels and edge enhancement at high light levels is obtained only by varying the weighting circuit gain. The design concepts and circuit layouts are also shown together with the performance data on test imagery.


Cost comparison of treating chronic hepatitis C genotype one with pegylated interferons in Ukraine.
Based on the pivotal trial showing no clinically relevant differences between pegylated interferon α-2b (Peg-α-2b) and α-2a (Peg-α-2a) combined with ribavirin for treatment of chronic hepatitis C virus (HCV) genotype 1 infection in Ukraine, a cost-minimization analysis was performed using a 1 year time horizon and both a health care and patients' perspective. A decision tree reflects treatment pathways. Drug costs were based on drug labeling and adjusted to the average body mass in Ukraine. Subgroup analysis was applied to deal with heterogeneity of patient's weight causing dose changes. A break-even price of Peg-α-2a and Peg-α-2b (based on the average dose) was calculated. Univariate sensitivity analyses and probabilistic sensitivity analysis were carried out to reflect decision uncertainty. For an average body weight, total medical costs per patient differ from US$9220 for Peg-α-2b to US$9513 for Peg-α-2a from a health care perspective, and from US$15,212 to US$15,696 from a patients' perspective. Sensitivity analyses show these results are robust. With average body weight, the break-even price of Peg-α-2b may be 7.3% higher than Peg-α-2a to have similar total costs.


From crystal and NMR structures, footprints and cryo-electron-micrographs to large and soft structures: nanoscale modeling of the nucleosomal stem.
The interaction of histone H1 with linker DNA results in the formation of the nucleosomal stem structure, with considerable influence on chromatin organization. In a recent paper [Syed,S.H., Goutte-Gattat,D., Becker,N., Meyer,S., Shukla,M.S., Hayes,J.J., Everaers,R., Angelov,D., Bednar,J. and Dimitrov,S. (2010) Single-base resolution mapping of H1-nucleosome interactions and 3D organization of the nucleosome. Proc. Natl Acad. Sci. USA, 107, 9620-9625], we published results of biochemical footprinting and cryo-electron-micrographs of reconstituted mono-, di- and tri-nucleosomes, for H1 variants with different lengths of the cationic C-terminus. Here, we present a detailed account of the analysis of the experimental data and we include thermal fluctuations into our nano-scale model of the stem structure. By combining (i) crystal and NMR structures of the nucleosome core particle and H1, (ii) the known nano-scale structure and elasticity of DNA, (iii) footprinting information on the location of protected sites on the DNA backbone and (iv) cryo-electron micrographs of reconstituted tri-nucleosomes, we arrive at a description of a polymorphic, hierarchically organized stem with a typical length of 20 ± 2 base pairs. A comparison to linker conformations inferred for poly-601 fibers with different linker lengths suggests, that intra-stem interactions stabilize and facilitate the formation of dense chromatin fibers.


Ileal Transposition in Rats Reduces Energy Intake, Body Weight, and Body Fat Most Efficaciously When Ingesting a High-Protein Diet.
Ileal transposition (IT) allows exploration of hindgut effects of bariatric procedures in inducing weight loss and reducing adiposity. Here we investigated the role of dietary macronutrient content on IT effects in rats. Male Lewis rats consuming one of three isocaloric liquid diets enriched with fat (HF), carbohydrates (HC), or protein (HP) underwent IT or sham surgery. Body weight, energy intake, energy efficiency, body composition, and (meal-induced) changes in plasma GIP, GLP-1, PYY, neurotensin, and insulin levels were measured. Following IT, HC intake remained highest leading to smallest weight loss among dietary groups. IT in HF rats caused high initial weight loss and profound hypophagia, but the rats caught up later, and finally had the highest body fat content among IT rats. HP diet most efficaciously supported IT-induced reduction in body weight and adiposity, but (as opposed to other diet groups) lean mass was also reduced. Energy efficiency decreased immediately after IT irrespective of diet, but normalized later. Energy intake alone explained variation in post-operative weight change by 80%. GLP-1, neurotensin, and PYY were upregulated by IT, particularly during (0-60 min) and following 17-h post-ingestive intake, with marginal diet effects. Thirty-day post-operative cumulative energy intake was negatively correlated to 17-h post-ingestive PYY levels, explaining 47% of its variation. Reduction in energy intake underlies IT-induced weight loss, with highest efficacy of the HP diet. PYY, GLP-1, and neurotensin levels are upregulated by IT, of which PYY may be most specifically related to reduced intake and weight loss after IT.


Apoptotic effects of the tyrosine kinase inhibitor, masitinib mesylate, on canine osteosarcoma cells.
Osteosarcoma (OSA) is the most common primary bone tumor in dogs and the guarded prognosis highlights the necessity to find new treatments. Masitinib mesylate is a highly selective tyrosine kinase inhibitor that predominantly targets c-Kit and PDGFR-α/β. This study evaluated the in-vitro activity of masitinib against three canine OSA cell lines after treatment with increasing concentrations of masitinib (0.1-50 µmol/l) at 24, 48, and 72 h. The IC50 values at 72 h for the three OSA cell lines (POS, HMPOS, and COS31) were determined to be 11.04, 7.09, and 9.74 µmol/l, respectively. In addition, increases in caspase-3/7 activity and transferase dUTP nick end labeling-positive cells indicated apoptotic cell death. Because increased levels of vascular endothelial growth factor are found in dogs with OSA, vascular endothelial growth factor in the supernatant was quantified. Overall, the study found that masitinib causes dose-time dependent OSA cell death in vitro through initiation of caspase-mediated apoptosis, which supports future OSA clinical trials.


Genetic structure of human populations in the British Isles.
Spatial patterns were studied for 36 allele frequencies representing 14 genetic systems (blood antigens, enzymes and serum proteins) in the United Kingdom and Irish Republic. The total number of data points over all systems and localities is 331. Patterns of genetic variation in space are graphically represented by one-dimensional and directional correlograms, and by interpolated allele-frequency surfaces. The data surfaces were examined by the various techniques of spatial autocorrelation analysis. Zones of rapid change across allele surfaces were discovered by the wombling method. Six allele frequency surfaces from four genetic systems exhibit significant spatial patterns. Only one pattern (IO; in the ABO system) may be described as purely clinal in an east-west direction; another (IB; in ABO) approximates a cline or at least north-south differentiation. A method was developed for testing the direction of maximal genetic autocorrelation. Two previously unrecorded patterns for the British Isles, north-south gradients for Rhesus and P, were detected. Twelve zones of rapid genetic change were discovered; some of these seem to reflect maritime and montane physical barriers as well as long-held cultural and linguistic differences, particularly between early Germanic and Celtic speakers. Moreover, some appear to reflect past historic events such as the invasions of Anglo-Saxons and Anglo-Normans.


Description and predictive factors of individual outcomes in a refugee camp based mental health intervention (Beirut, Lebanon).
There is little evidence on the effectiveness of services for the care of people with mental disorders among refugee populations. Médecins sans Frontières (MSF) has established a mental health centre in a mixed urban-refugee population in Beirut to respond to the significant burden of mental health problems. Patients received comprehensive care through a multidisciplinary team. A cohort of people with common and severe mental disorders has been analysed between December 2008 and June 2011 to evaluate individual outcomes of treatment in terms of functionality. All patients diagnosed with mental disorders were included in the study. The Global Assessment of Functioning (GAF) and the Self Reporting Questionnaire-20 items (SRQ 20) were used as tools for baseline assessment, monitoring and evaluation of patients. Predictors of evolution of SRQ20 and GAF over visits were explored using a linear mixed model. Up to June 2011, 1144 patients were followed, 63.7% of them Lebanese, 31.8% Palestinians and 1.2% Iraqis. Females represented 64.2% of the patient population. Mean age was 39.2 years (28.5-46.5). The most frequent primary diagnoses were depressive disorders (28.8%), anxiety disorders (15.6%) and psychosis (11.5%). A lower baseline SRQ20 score/higher baseline GAF score (indicators of severity), being diagnosed with anxiety (compared to being diagnosed with depression or psychosis) and a higher level of education were associated with better outcomes. In this MSF program, we observed a significant decrease of SRQ20 individual scores and a significant increase of individual GAF scores. This corresponded to an improvement in the functionality of our patients. Analysis of the predictors of this positive evolution indicates that we need to adapt our model for the more severe and less educated patients. It also makes us reflect on the length of the individual follow-up. Further research could include a qualitative evaluation of the intervention. Results of this study have been presented at the World Congress of the World Federation for Mental Health in Cape Town, October 2011.


Bovine neonatal pancytopenia--comparative proteomic characterization of two BVD vaccines and the producer cell surface proteome (MDBK).
Bovine neonatal pancytopenia (BNP) is a disease syndrome in newborn calves of up to four weeks of age, first observed in southern Germany in 2006. By now, cases have been reported in several countries around the globe. Many affected calves die within days due to multiple haemorrhages, thrombocytopenia, leukocytopenia and bone marrow depletion. A certain vaccine directed against Bovine Virus Diarrhoea Virus (BVDV) was recently shown to be associated with BNP pathogenesis. Immunized cows develop alloantibodies that are transferred to newborn calves via colostrum intake. In order to further elucidate BNP pathogenesis, the purpose of this study was to characterize and compare the protein composition of the associated vaccine to another vaccine directed against BVDV not related to BNP and the cell surface proteome of MDBK (Madin-Darby Bovine Kidney) cells, the cell line used for production of the associated vaccine. By SDS-PAGE and mass spectrometry, we were able to detect several coagulation-related and immune modulatory proteins, as well as cellular and serum derived molecules being shared between the associated vaccine and MDBK cells. Furthermore, the number of proteins identified in the BNP related vaccine was almost as high as the number of surface proteins detected on MDBK cells and exceeded the amount of proteins identified in the non-BNP related vaccine over 3.5 fold. The great amount of shared cellular and serum derived proteins confirm that the BNP associated vaccine contained many molecules originating from MDBK cells and vaccine production. The respective vaccine was not purified enough to prevent the development of alloantibodies. To narrow down possible candidate proteins, those most likely to represent a trigger for BNP pathogenesis are presented in this study, giving a fundament for further analysis in future research.


Enzymatic methylation of arsenic compounds. III. The marmoset and tamarin, but not the rhesus, monkeys are deficient in methyltransferases that methylate inorganic arsenic.
The methylation of inorganic arsenic to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) have been generally considered to be the major pathway for inorganic arsenic biotransformation and detoxification. Yet, when arsenate/arsenite is injected into the Callithrix jacchus (marmoset) monkey or chimpanzee, monomethylarsonic acid and dimethylarsinic acid are not found in the urine. With the development of a rapid assay for the methyltransferases of arsenic metabolism, we have investigated the methyltransferases of the marmoset monkey liver. We have found that the marmoset, a New World animal, is deficient in liver arsenite and monomethylarsonic acid methyltransferase activities. However, the rhesus monkey, an Old World animal, has ample amounts of such methyltransferase activities. The tamarin, another New World species, is also deficient in these methyltransferases. Polymorphism and deficiency of these methyltransferases may have allowed high levels of arsenite to be maintained in the blood and liver of the marmoset and tamarin. Such high levels of arsenite may have been selective for survival of the species. The rhesus liver methyltransferases for arsenite and MMA have been purified and found to have some properties different from those of the previously reported purified rabbit liver activities. The rhesus and rabbit liver arsenite and MMA methyltransferases are devoid of catechol O-methyltransferase activity.


Discovery of ordered and quasi-ordered photonic crystal structures in the scales of the beetle Eupholus magnificus.
The outer wing casings (elytra) of the weevil Eupholus magnificus are marked by yellow and blue bands. We have investigated the scales covering the elytra by using microspectrophotometry, imaging scatterometry, scanning electron microscopy and Fourier transform analysis. We demonstrate that the scales in the yellow elytral bands comprise highly ordered 3D photonic crystal structures, whereas the scales of the blue bands comprise quasi-ordered 3D photonic structures. Both systems, highly contrasting in their periodic order, create approximately angle-independent colour appearances in the far-field. The co-existence of these two contrasting forms of 3D structural order in the same single species is certainly uncommon in natural biological systems and has not been reported in the photonic literature.