T-Duality and Two-Loop Renormalization Flows

Manifest T-duality covariance of the one-loop renormalization group flows is shown for a generic bosonic sigma model with an abelian isometry, by referring a set of previously derived consistency conditions to the tangent space of the target. For a restricted background, T-duality transformations are then studied at the next order, and the ensuing consistency conditions are found to be satisfied by the two-loop Weyl anomaly coefficients of the model. This represents an extremely non-trivial test of the covariance of renormalization group flows under T-duality, and a stronger condition than T-duality invariance of the string background effective action.Comment: 18 pp., plain TeX + harvmac. Typos in Eqs. (4.3), (4.5) and (4.7) corrected, and references adde

Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso. An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies

Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria

Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380

Variegate porphyria in South Africa, 1688 - 1996 - new developments in an old disease

Variegate porphyria, an autosomal dominant inherited trait resulting in decreased activity of protoporphyrinogen oxidase, the penuttimate haem biosynthetic enzyme, is characterised clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. The disease has an exceptionally high frequency in South Africa,owing to a founder effect. The specific mutation in the protoporphynnogen oxidase gene sequence which represents this founder gene has been identified. Genetic diagnosis is therefore now possible in families in whom the gene defect is known. However, the exact nature and degree of activity of the porphyria can only be determined by detailed quantitative biochemical analysis of excreted porphyrins. The relative contributions of the acute attack and the skin disease to the total disease burden of patients with variegate porphyria is not static, and in South Africa there have been significant changes over the past 25 years, with fewer patients presenting with acute attacks, leaving a greater proportion to present with skin disease or to remain asymptomatic with the diagnosis being made in the laboratory. The most common precipitating cause of the acute attack of VP is administration of porphyrinogenic drugs. Specific suppression of haem synthesis with intravenous haem arginate is the most useful treatment of a moderate or severe acute attack. Although cutaneous lesions are limited to the sun-exposed areas, management of the skin disease of VP remains inadequate

Strong Gametocytocidal Effect of Methylene Blue-Based Combination Therapy against Falciparum Malaria: A Randomised Controlled Trial

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso.An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days.The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline.MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies.(ClinicalTrials.gov) NCT00354380

Lepton pairs from thermal mesons

We study the net dielectron production rates from an ensemble of thermal mesons, using an effective Lagrangian to model their interaction. The coupling between the electromagnetic and the hadronic sectors is done through the vector meson dominance approach. For the first time, a complete set of light mesons is considered. We include contributions from decays of the type V~(PS)~$\rightarrow$~PS~(V)~+~$e^+~e^-$, where V is a vector meson and PS is a pseudoscalar, as well as those from binary reactions PS~+~PS, V~+~V, and V~+~PS~$\rightarrow~e^+e^-$. Direct decays of the type V~$\rightarrow~e^+ e^-$ are included and shown to be important. We find that the dielectron invariant mass spectrum naturally divides in distinct regions: in the low mass domain the decays from vector and pseudoscalar mesons form the dominant contribution. The pion--pion annihilation and direct decays then pick up and form the leading signal in an invariant mass region that includes the $\rho - \omega$ complex and extends up to the $\phi$. Above invariant mass $M\ \approx$~1~GeV other two-body reactions take over as the prominent mechanisms for lepton pair generation. These facts will have quantitative bearing on the eventual identification of the quark--gluon plasma.Comment: In ReVTeX 3.0, 9 figs. available from above email address. McGill 93/8, TPI-MINN-93/19-

Fermion sea along the sphaleron barrier

In this revised version we have improved the treatment of the top and bottom quark mass. This leads to slight changes of the numerical results, especially of those presented in Fig.4. The discussion of the numerical procedure and accuracy has been extended.Comment: 39 pages (LaTex) plus 5 figures (uuencoded postscript files); RUB-TPII-62/93, to appear in Phys.Rev.

Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso ( CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [ 95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa

Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841]

BACKGROUND: Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. OBJECTIVES: The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. METHODS: In this hospital-based randomized controlled trial, 226 children (6–59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. RESULTS: No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. CONCLUSION: MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs

Routing of western Canadian Plains runoff during the 8.2 ka cold event

The collapse of the Laurentide Ice Sheet over Hudson Bay ∼8.47 ka allowed the rapid drainage of glacial Lake Agassiz into the Labrador Sea, an event identified as causing a reduction in Atlantic meridional overturning circulation (AMOC) and the 8.2 ka cold event. Atmosphere-ocean models simulations based on this forcing, however, fail to reproduce several characteristics of this event, particularly its duration. Here we use planktonic foraminifera U/Ca records to document the routing of western Canadian Plains runoff that accompanied ice-sheet collapse. Geochemical modeling of the ∼7 nmol/mol increase in U/Ca at the opening of Hudson Bay indicates an increase in freshwater discharge of 0.13 ± 0.03 Sverdrups (106 m3 s−1) from routing, a sufficient magnitude to cause an AMOC reduction. We suggest that this routing event suppressed AMOC strength for several centuries after the drainage of Lake Agassiz, explaining multi-centennial climate anomalies associated with the 8.2 ka cold event