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Evidence from natural magmas and mantle xenoliths argues that fluids in the system C-0-H exercise important influences on petrogenetic processes in the Earth's upper mantle. In this thesis, experimental, spectroscopic and theoretical constraints are applied to provide the necessary basis for understanding the nature of mantle melting as a function of oxygen fugacity (f02) in the model system \peridotite\"-C-0-H. Until very recently most petrogenetic models were based on the assumption that f02 -conditions in magma source-regions of the upper mantle were relatively oxidised lying near the f02 defined by the synthetic assemblage fay a li te-magneti te-quartz (FMQ). This was cons is tent with the petrogenetic role inferred for oxidised co2-H20 volatiles and carbonated peridotite. However if magma generation involving volatile components takes place in a reduced environment for example at f02's near the synthetic iron-wustite (IW) oxygen buffer - as suggested by intrinsic f02 measurements on mantle-derived minerals - then in the model system \"peridotite\"-C-0-H volatiles will be dominantly CH4 > H20 > H2 mixtures and crystalline carbonates will not be stable relative to diamond or graphite. The nature of mantle melts produced under reduced conditions is expected to be very different from melts originating in an oxidised environment. To investigate the role of reduced volatiles in upper mantle processes a two-fold approach has been pursued. Firstly a thermodynamic model for supercritical C-0-H fluids under elevated PT conditions was derived. Available volumetric data for the important species: H20 C02 CO H2 CH4 and C2H6 were used to calibrate an MRK-type equation of state. Using fugacity coefficients derived from the MRK-equation the distribution of C-0-H species as a function of PT and f02 has been determined. Application of this model to fluids incorporated in natural diamond (perhaps the only unequivocal example of upper mantle fluids) suggests that the majority of natural diamonds and coexisting C-0-H fluids were at equilibrium in the mantle under redox conditions near or slightly above f02 = IW. A genetic link between methane-bearing fluids and diamond is indicated. The second approach taken in this study was directed at understanding the nature of mantle melting in the presence of reduced volatile species. Because little is known of the mechanism of reduced volatile interaction with silicate systems an investigation of the CH4-H2-C2H6 fluid solubility mechanism in aluminosilicate melts was undertaken. Jadeite and sodamelilite composition melts were saturated with a C-H fluid at P = 30 kbar and Fourier transform infrared (FTIR) spectra of the resultant high-P quenched glasses were recorded. FTIR spectra distinguish both oxidised and reduced components dissolved in the melt as predicted from theoretical considerations. Low total carbon concentrations (

Background:WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission ofPlasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. Methods:We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicatedP falciparuminfection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for theG6PDc.202T allele, the cause of the G6PD-deficient A− variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether–lumefantrine or dihydroartemisinin–piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin Findings:Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether–lumefantrine plus single low-dose primaquine group, 286 to the artemether–lumefantrine plus placebo group, 283 to the dihydroartemisinin–piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin–piperaquine plus placebo group). Genotyping ofG6PDidentified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study—these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference −0·66%, 95% CI −1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (−0·014%, −0·68 to 0·65; p=0·97). Interpretation:Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected withP falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa.

C9ORF78 is a poorly characterized protein found in diverse eukaryotes. Previous work indicated overexpression of hC9ORF78 (aka HCA59) in malignant tissues indicating a possible involvement in growth regulatory pathways. Additional studies in fission yeast and humans uncover a potential function in regulating the spliceosome. In studies of GFP-tagged hC9ORF78 we observed a dramatic reduction in protein abundance in cells grown to confluence and/or deprived of serum growth factors. Serum stimulation induced synchronous re-expression of the protein in HeLa cells. This effect was also observed with the endogenous protein. Overexpressing either E2F1 or N-Myc resulted in elevated hC9ORF78 expression potentially explaining the serum-dependent upregulation of the protein. Immunofluorescence analysis indicates that hC9ORF78 localizes to nuclei in interphase but does not appear to concentrate in speckles as would be expected for a splicing protein. Surprisingly, a subpopulation of hC9ORF78 co-localizes with ACA, Mad1 and Hec1 in mitotic cells suggesting that this protein may associate with kinetochores or centromeres. Furthermore, knocking-down hC9ORF78 caused mis-alignment of chromosomes in mitosis. These studies uncover novel mitotic function and subcellular localization of cancer antigen hC9ORF78.SUMMARY STATEMENThC9ORF78 regulates chromosome segregation.

Background The WHO recommends single low-dose primaquine (SLDPQ, 0.25 mg/kg body weight) in falciparum-infected patients to block malaria transmission and contribute to eliminating multidrug resistant Plasmodium falciparum from the Greater Mekong Sub region (GMS). However, the anxiety regarding PQ-induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency (G6PDd) has hindered its use. Therefore, we assessed the tolerability of SLDPQ in Cambodia to inform national policy. Methods This open randomised trial of dihydroartemisinin-piperaquine (DHAPP) + SLDPQ vs. DHAPP alone recruited Cambodians aged ≥1 year with acute uncomplicated P. falciparum. Randomisation was 4:1 DHAPP+SLDPQ: DHAPP for G6PDd patients and 1:1 for G6PDn patients, according to the results of the qualitative fluorescent spot test. Definitive G6PD status was determined by genotyping. Day (D) 7 haemoglobin (Hb) concentration was the primary outcome measure. Results One hundred nine patients (88 males, 21 females), aged 4–76 years (median 23) were enrolled; 12 were G6PDd Viangchan (9 hemizygous males, 3 heterozygous females). Mean nadir Hb occurred on D7 [11.6 (range 6.4 ─ 15.6) g/dL] and was significantly lower (p = 0.040) in G6PDd (n = 9) vs. G6PDn (n = 46) DHAPP+SLDPQ recipients: 10.9 vs. 12.05 g/dL, Δ = -1.15 (95% CI: -2.24 ─ -0.05) g/dL. Three G6PDn patients had D7 Hb concentrations

Objectives: Some TKA designs show a “paradoxical” anterior translation of the femur and lateral pivoting with increasing flexion, which is not observed in native knees. Altered kinematics can lead to increased patello-femoral contact forces and problems of the extensor mechanism. TKA designs[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018)

The goal to eliminate malaria from the Asia-Pacific by 2030 will require the safe and widespread delivery of effective radical cure of malaria. In October 2017, the Asia Pacific Malaria Elimination Network Vivax Working Group met to discuss the impediments to primaquine (PQ) radical cure, how these can be overcome and the methodological difficulties in assessing clinical effectiveness of radical cure. The salient discussions of this meeting which involved 110 representatives from 18 partner countries and 21 institutional partner organizations are reported. Context specific strategies to improve adherence are needed to increase understanding and awareness of PQ within affected communities; these must include education and health promotion programs. Lessons learned from other disease programs highlight that a package of approaches has the greatest potential to change patient and prescriber habits, however optimizing the components of this approach and quantifying their effectiveness is challenging. In a trial setting, the reactivity of participants results in patients altering their behaviour and creates inherent bias. Although bias can be reduced by integrating data collection into the routine health care and surveillance systems, this comes at a cost of decreasing the detection of clinical outcomes. Measuring adherence and the factors that relate to it, also requires an in-depth understanding of the context and the underlying sociocultural logic that supports it. Reaching the elimination goal will require innovative approaches to improve radical cure for vivax malaria, as well as the methods to evaluate its effectiveness.

Visceral leishmaniasis (VL) is endemic in Iran and is caused predominantly by Leishmania infantum, but L. tropica is emerging as an important cause. We studied the intra-species population structure of Leishmania spp. causing VL in southwest Iran by sequence analysis of the internal transcribed spacer (ITS) 1 of DNA samples from 29 bone marrow aspiration smears. L. infantum (n = 25) and L. tropica (n = 4) were identified, consisting of 10 and three ITS1 sequence types (STs), respectively. Compared to GenBank ITS1 STs, our L. infantum parasites displayed high heterogeneity but less heterogeneity compared than northwest Iranian isolates. VL affects mostly nomadic populations in southwest Iran, and their mobility may explain partly the L. infantum heterogeneity. The VL causing L. tropica was also genetically heterogeneous but genetically indistinguishable from L. tropica strains causing anthroponotic cutaneous leishmaniasis from southwest Iran.

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.

Since 2001, the incidence and mortality of malaria caused by Plasmodium falciparum have declined. However, this trend has not been seen with Plasmodium vivax which has biological features. Severe vivax malaria is increasingly reported in endemic countries even though P. vivax has been thought of as a benign disease. Diagnosis is challenging : the usual rapid diagnostic tests are less sensitive in detecting P. vivax and there is no test for the detection of the dormant forms (hypnozoites). The treatment of the acute phase is an artemisinin based combination, e.g. artemetherlumefantrine. Primaquine, which is the only currently available treatment against hypnozoites for the prevention of relapses, may trigger acute haemolytic anaemia in individuals with G6PD deficiency.>br/>Depuis 2001, l’incidence et la mortalité de la malaria à Plasmodium falciparum ont diminué. Toutefois, cette tendance n’est pas suivie par Plasmodium vivax, qui présente certaines particularités biologiques. Anciennement considérée comme bénigne, de plus en plus de cas sévères de malaria à P. vivax sont rapportés dans les pays endémiques. Le diagnostic peut être difficile : les tests rapides usuels sont moins sensibles pour détecter P. vivax, et il n’en existe aucun pour la détection des formes dormantes (hypnozoïtes). Le traitement de la crise aiguë est une combinaison thérapeutique à base d’artémisinine, par exemple l’artéméther-luméfantrine. La prévention des rechutes repose sur l’administration de la primaquine, seul traitement actuellement disponible contre les hypnozoïtes et limité par le risque de crise hémolytique en cas de déficit en glucose-6-phosphate-déshydrogénase (G6PD).

Vascular complications of diabetes represent the leading cause of morbidity and mortality in affected patients. Production of reactive oxygen species is increased in diabetic patients, especially in those with poor glycemic control. Reactive oxygen species affect vascular smooth muscle cell growth and migration, endothelial function, including abnormal endothelium-dependent relaxation and expression of a proinflammatory phenotype, and modification of the extracellular matrix. All of these events contribute to the development of diabetic microvascular and macrovascular complications, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.

Clinical hypertensive vascular disease is the result of complex alterations in the biology of the cellular components of the arterial wall. In this review, the hypothesis will be put forth that elevated blood pressure induces an inflammatory state in the arterial wall through both humoral and mechanical signaling pathways. The generation of reactive oxygen species and subsequent upregulation of redox-sensitive proinflammatory gene products are common endpoints of these pathways. Subsequent adaptive and maladaptive responses of the wall occur as a result of the integration of the humoral and mechanical stimuli.

OBJECTIVES: Long-term chemoprophylaxis using neuraminidase inhibitors may be needed during influenza epidemics but safety data are limited to several weeks. We sought to assess the tolerability of oseltamivir and zanamivir as primary prophylaxis over 16 weeks. METHODS: We conducted a parallel group, double blind, 2 (active drug) :1 (placebo) randomized trial of oral oseltamivir/placebo or inhaled zanamivir/placebo over 16 weeks in healthy, Thai hospital professionals at two Bangkok hospitals. The primary endpoint was study withdrawal due to drug-related (possibly, probably, definitely) serious or adverse events (AEs) graded ≥ 2. RESULTS: Recruited subjects numbered 129 oseltamivir/65 placebo and 131 zanamivir/65 placebo. A total of 102 grade ≥ 2 AEs were reported or detected in 69 subjects: 23/129 (17.8%) versus 15/65 (23.1%) (P=0.26), and 23/131 (17.6%) versus 8/65 (12.3%) (P=0.28). Intercurrent infections/fevers [26/102 (25.5%)], abnormal biochemistry [25/102 (24.5%)] and gastrointestinal symptoms [18/102 (17.6%)] were the most frequently reported AEs. There were no drug-related study withdrawals. Eight serious AEs were all due to intercurrent illnesses. Laboratory, lung function and ECG parameters were similar between drugs and placebos. CONCLUSIONS: Oseltamivir and zanamivir were well tolerated in healthy hospital professionals. Both drugs can be recommended for primary influenza prophylaxis for up to 16 weeks.

Fragestellung: Patienten mit Knieinstabilitäten setzen zur Stabilisierung des Gelenkes während einer dynamischen Bewegung erhöhte Muskelkräfte ein. Es ist unbekannt, ob die aktive kinematische Gelenkstabilität der gesunden Gegenseite erreicht werden kann. Um zu verstehen, ob[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2013)

Fragestellung: Der Prozess der Frakturheilung führt zur narbenfreien Heilung und Wiederherstellung der ursprünglichen Struktur und Funktion. Neuere Studien lassen einen entscheidenden Einfluss der T-Zellen des adaptativen Immunsystems auf das Ergebnis der Knochenheilung vermuten. In dieser[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2013)

Fragestellung: Das externe Adduktionsmoment (EAM) gilt als indirektes Maß für die mediale Knie-Kontaktkraft (Fmed). Die empirische Beweislage für einen Zusammenhang zwischen diesen Größen ist jedoch auf Untersuchungen beim Gehehen eines Patienten beschränkt [ref:1],[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2012)

Questionnaire: While the multi-factorial nature of patello-femoral (PF) instability is widely recognized, little is known about the competence of the quadriceps and its role in providing active joint stabilization in patients with PF instability. However, any imbalance between the medial and lateral[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 75. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 97. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 52. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Fragestellung: Bisher ist es weitgehend unklar, inwieweit die verschiedenen Prothesentypen die physiologischen Bewegungsmuster des Kniegelenks wiederherstellen können. Bei rotierenden Plattformen wird die Relevanz der Möglichkeit der freien tibiofemoralen Rotation kontrovers diskutiert bzw.[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 73. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 95. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 50. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Fragestellung: In dieser Studie sollte geklärt werden, wie die Gelenkbiomechanik bei wichtigen Alltagsaktivitäten von der Vorspannung des Transplantats nach MPFL Rekonstruktion abhängt, insbesondere hinsichtlich des Risikos einer medialen Gelenküberlastung. Methodik: An 6 Kadaverknien[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 73. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 95. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 50. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Fragestellung: Die Bestimmung der Achsverhältnisse der unteren Extremitäten spielt eine wesentliche Rolle in der Planung und Überwachung des Erfolges therapeutischer Interventionen am Kniegelenk. Bei Verwendung von Röntgenbildern oder CTs zur Bestimmung der Achsverhältnisse [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 73. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 95. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 50. Tagung des Berufsverbandes der Fachärzte für Orthopädie